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1.  Support for immunization registries among parents of vaccinated and unvaccinated school-aged children: a case control study 
BMC Public Health  2006;6:236.
Background
Immunizations have reduced childhood vaccine preventable disease incidence by 98–100%. Continued vaccine preventable disease control depends on high immunization coverage. Immunization registries help ensure high coverage by recording childhood immunizations administered, generating reminders when immunizations are due, calculating immunization coverage and identifying pockets needing immunization services, and improving vaccine safety by reducing over-immunization and providing data for post-licensure vaccine safety studies. Despite substantial resources directed towards registry development in the U.S., only 48% of children were enrolled in a registry in 2004. Parental attitudes likely impact child participation. Consequently, the purpose of this study was to assess the attitudes of parents of vaccinated and unvaccinated school-aged children regarding: support for immunization registries; laws authorizing registries and mandating provider reporting; opt-in versus opt-out registry participation; and financial worth and responsibility of registry development and implementation.
Methods
A case control study of parents of 815 children exempt from school vaccination requirements and 1630 fully vaccinated children was conducted. Children were recruited from 112 elementary schools in Colorado, Massachusetts, Missouri, and Washington. Surveys administered to the parents, asked about views on registries and perceived utility and safety of vaccines. Parental views were summarized and logistic regression models compared differences between parents of exempt and vaccinated children.
Results
Surveys were completed by 56.1% of respondents. Fewer than 10% of parents were aware of immunization registries in their communities. Among parents aware of registries, exempt children were more likely to be enrolled (65.0%) than vaccinated children (26.5%) (p value = 0.01). A substantial proportion of parents of exempt children support immunization registries, particularly if registries offer choice for participation. Few parents of vaccinated (6.8%) and exempt children (6.7%) were aware of laws authorizing immunization registries. Support for laws authorizing registries and requiring health care providers to report to registries was more common among parents of vaccinated than exempt children. Most parents believed that the government, vaccine companies or insurance companies should pay for registries.
Conclusion
Parental support for registries was relatively high. Parental support for immunization registries may increase with greater parental awareness of the risks of vaccine preventable diseases and utility of vaccination.
doi:10.1186/1471-2458-6-236
PMCID: PMC1592086  PMID: 16995946
2.  A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt 
PLoS Medicine  2010;7(5):e1000270.
Analysis of a telephone survey by Gina Ogilvie and colleagues identifies the parental factors associated with HPV vaccine uptake in a school-based program in Canada.
Background
Information on factors that influence parental decisions for actual human papillomavirus (HPV) vaccine receipt in publicly funded, school-based HPV vaccine programs for girls is limited. We report on the level of uptake of the first dose of the HPV vaccine, and determine parental factors associated with receipt of the HPV vaccine, in a publicly funded school-based HPV vaccine program in British Columbia, Canada.
Methods and Findings
All parents of girls enrolled in grade 6 during the academic year of September 2008–June 2009 in the province of British Columbia were eligible to participate. Eligible households identified through the provincial public health information system were randomly selected and those who consented completed a validated survey exploring factors associated with HPV vaccine uptake. Bivariate and multivariate analyses were conducted to calculate adjusted odds ratios to identify the factors that were associated with parents' decision to vaccinate their daughter(s) against HPV. 2,025 parents agreed to complete the survey, and 65.1% (95% confidence interval [CI] 63.1–67.1) of parents in the survey reported that their daughters received the first dose of the HPV vaccine. In the same school-based vaccine program, 88.4% (95% CI 87.1–89.7) consented to the hepatitis B vaccine, and 86.5% (95% CI 85.1–87.9) consented to the meningococcal C vaccine. The main reasons for having a daughter receive the HPV vaccine were the effectiveness of the vaccine (47.9%), advice from a physician (8.7%), and concerns about daughter's health (8.4%). The main reasons for not having a daughter receive the HPV vaccine were concerns about HPV vaccine safety (29.2%), preference to wait until the daughter is older (15.6%), and not enough information to make an informed decision (12.6%). In multivariate analysis, overall attitudes to vaccines, the impact of the HPV vaccine on sexual practices, and childhood vaccine history were predictive of parents having a daughter receive the HPV vaccine in a publicly funded school-based HPV vaccine program. By contrast, having a family with two parents, having three or more children, and having more education was associated with a decreased likelihood of having a daughter receive the HPV vaccine.
Conclusions
This study is, to our knowledge, one of the first population-based assessments of factors associated with HPV vaccine uptake in a publicly funded school-based program worldwide. Policy makers need to consider that even with the removal of financial and health care barriers, parents, who are key decision makers in the uptake of this vaccine, are still hesitant to have their daughters receive the HPV vaccine, and strategies to ensure optimal HPV vaccine uptake need to be employed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, globally, more than a quarter of a million women die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse. There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Although most people become infected with HPV at some time in their life, most never know they are infected. However, some HPV types cause harmless warts on the skin or around the genital area and several—in particular, HPV 16 and HPV 18, so-called high-risk HPVs—can cause cervical cancer. HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries in recent decades by detecting the cancer early when it can be treated; but it would be better to prevent cervical cancer ever developing. Because HPV is necessary for the development of cervical cancer, vaccination of girls against HPV infection before the onset of sexual activity might be one way to do this. Scientists recently developed a vaccine that prevents infection with HPV 16 and HPV 18 (and with two HPVs that cause genital warts) and that should, therefore, reduce the incidence of cervical cancer. Publicly funded HPV vaccination programs are now planned or underway in several countries; but before girls can receive the HPV vaccine, parental consent is usually needed, so it is important to know what influences parental decisions about HPV vaccination. In this study, the researchers undertake a telephone survey to determine the uptake of the HPV vaccine by 11-year-old girls (grade 6) in British Columbia, Canada, and to determine the parental factors associated with vaccine uptake; British Columbia started a voluntary school-based HPV vaccine program in September 2008.
What Did the Researchers Do and Find?
In early 2009, the researchers contacted randomly selected parents of girls enrolled in grade 6 during the 2008–2009 academic year and asked them to complete a telephone survey that explored factors associated with HPV vaccine uptake. 65.1% of the 2,025 parents who completed the survey had consented to their daughter receiving the first dose of HPV vaccine. By contrast, more than 85% of the parents had consented to hepatitis B and meningitis C vaccination of their daughters. Nearly half of the parents surveyed said their main reason for consenting to HPV vaccination was the effectiveness of the vaccine. Conversely, nearly a third of the parents said concern about the vaccine's safety was their main reason for not consenting to vaccination and one in eight said they had been given insufficient information to make an informed decision. In a statistical analysis of the survey data, the researchers found that a positive parental attitude towards vaccination, a parental belief that HPV vaccination had limited impact on sexual practices, and completed childhood vaccination increased the likelihood of a daughter receiving the HPV vaccine. Having a family with two parents or three or more children and having well-educated parents decreased the likelihood of a daughter receiving the vaccine.
What Do These Findings Mean?
These findings provide one of the first population-based assessments of the factors that affect HPV vaccine uptake in a setting where there are no financial or health care barriers to vaccination. By identifying the factors associated with parental reluctance to agree to HPV vaccination for their daughters, these findings should help public-health officials design strategies to ensure optimal HPV vaccine uptake, although further studies are needed to discover why, for example, parents with more education are less likely to agree to vaccination than parents with less education. Importantly, the findings of this study, which are likely to be generalizable to other high-income countries, indicate that there is a continued need to ensure that the public receives credible, clear information about both the benefits and long-term safety of HPV vaccination.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000270.
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about HPV
The UK National Health Service Choices website has pages on cervical cancer and on HPV vaccination
More information about cervical cancer and HPV vaccination is available from the Macmillan cancer charity
ImmunizeBC provides general information about vaccination and information about HPV vaccination in British Columbia
MedlinePlus provides links to additional resources about cervical cancer (in English and Spanish)
doi:10.1371/journal.pmed.1000270
PMCID: PMC2864299  PMID: 20454567
3.  Parents’ Internet use for information about HPV vaccine 
Vaccine  2011;30(25):3757-3762.
Purpose
The Internet is an increasingly common source of health-related information. We sought to examine associations between parents’ Internet information-seeking and their knowledge, attitudes and beliefs about human papillomavirus (HPV) vaccine.
Methods
We interviewed parents within a year after approval of HPV vaccine for females and males. Participants were North Carolina parents with daughters ages 10–18 surveyed by telephone in Fall 2007 (n=773); and a national sample of parents with sons ages 11–17 surveyed online in Fall 2010 (n=115). We used multivariate regression to examine associations of past and intended Internet seeking for HPV vaccine information with knowledge and health belief model-related constructs.
Results
Among parents of daughters, having heard of HPV vaccine through the Internet (8%) was associated with higher HPV knowledge, perceived likelihood of HPV, and vaccination willingness, and with receiving a doctor’s recommendation. It was also associated with lower perceived vaccine harms, uncertainty, and anticipated regret. Parents of sons who heard of HPV vaccine through the Internet (10%) perceived greater barriers to vaccination than parents who learned about HPV vaccine for males through other sources. Intended future Internet information-seeking among parents of daughters (69%) was more likely if they perceived a lower likelihood that their daughters would get HPV if they were vaccinated (all p<.05).
Conclusions
Our findings suggest a positive influence of accessing information on the Internet about HPV vaccine. It was associated with higher knowledge and mostly positive parental attitudes and beliefs.
doi:10.1016/j.vaccine.2011.11.113
PMCID: PMC3346865  PMID: 22172505
HPV vaccine; adolescent health; Internet; health belief model
4.  The Association Between Intentional Delay of Vaccine Administration and Timely Childhood Vaccination Coverage 
Public Health Reports  2010;125(4):534-541.
SYNOPSIS
Objectives
We evaluated the association between intentional delay of vaccine administration and timely vaccination coverage.
Methods
We used data from 2,921 parents of 19- to 35-month-old children that included parents' reports of intentional delay of vaccine administration. Timely vaccination was defined as administration with ≥4 doses of diphtheria, tetanus, and pertussis; ≥3 doses of polio vaccine; ≥1 dose of measles, mumps, and rubella vaccine; ≥3 doses of Haemophilus influenzae type b vaccine; ≥3 doses of hepatitis B vaccine; and ≥1 dose of varicella vaccine by 19 months of age, as reported by vaccination providers.
Results
In all, 21.8% of parents reported intentionally delaying vaccinations for their children. Among parents who intentionally delayed, 44.8% did so because of concerns about vaccine safety or efficacy and 36.1% delayed because of an ill child. Children whose parents intentionally delayed were significantly less likely to receive all vaccines by 19 months of age than children whose parents did not delay (35.4% vs. 60.1%, p<0.05). Parents who intentionally delayed were significantly more likely to have heard or read unfavorable information about vaccines than parents who did not intentionally delay (87.6% vs. 71.9%, p<0.05). Compared with parents who intentionally delayed only because their child was ill, parents who intentionally delayed only because of vaccine safety or efficacy concerns were significantly more likely to seek additional information about their decision from the Internet (11.4% vs. 1.1%, p<0.05), and significantly less likely to seek information from a doctor (73.9% vs. 93.9%, p<0.05).
Conclusions
Intentionally delayed vaccine doses are not uncommon. Children whose parents delay vaccinations may be at increased risk of not receiving all recommended vaccine doses by 19 months of age and are more vulnerable to vaccine-preventable diseases. Providers should consider strategies such as educational materials that address parents' vaccine safety and efficacy concerns to encourage timely vaccination.
PMCID: PMC2882604  PMID: 20597453
5.  Ensemble Modeling of the Likely Public Health Impact of a Pre-Erythrocytic Malaria Vaccine 
PLoS Medicine  2012;9(1):e1001157.
Using an ensemble modeling approach, Thomas Smith and colleagues find that targeted mass vaccination with a pre-erythrocytic malaria vaccine RTS,S in low-transmission settings might have better health effects than vaccination through national EPI programs.
Background
The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure.
Methods and Findings
An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage.
Conclusions
In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear. The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that there are over 200 million cases of malaria each year, and that more than three-quarters of a million people (mostly children living in sub-Saharan Africa) die as a result. Several Plasmodium parasites cause malaria, the most deadly being Plasmodium falciparum. Plasmodium parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause recurring fever and can cause life-threatening organ damage. Malaria transmission can be prevented by using insecticides to control the mosquitoes that spread the parasite and by sleeping under insecticide-treated bed nets to avoid mosquito bites. Treatment with antimalarial drugs also reduces transmission. Together, these preventative measures have greatly reduced the global burden of malaria over recent years, but a malaria vaccine could be a valuable additional tool against the disease. At present there is no licensed malaria vaccine, but one promising vaccine—RTS,S—is currently undergoing phase III clinical trials (the last stage of testing before licensing) in infants and children in seven African countries.
Why Was This Study Done?
If the RTS,S vaccine fulfills its promise and is licensed, how should it be used to maximize its effect on the global malaria burden? Should it be given through the World Health Organization's Expanded Programme on Immunization (EPI), which aims to provide universal access to immunization against several infectious diseases during the first three months of life, for example, or through mass vaccination campaigns? Individual mathematical models have been used to investigate this type of question, but the predictions made by these models may be inaccurate because malaria immunity is poorly understood, because little is known about the levels of variability (heterogeneity) in host responses to malaria infection and in malaria transmission, and because it is unclear what the structure of models used to predict vaccine efficacy should be. In this study, the researchers use an “ensemble” approach to model the likely public health impact of the RTS,S malaria vaccine. That is, they simultaneously consider the effect of the vaccine in multiple models of P. falciparum dynamics. Ensemble modeling is widely used in weather forecasting and has been used to investigate several other infectious diseases.
What Did the Researchers Do and Find?
The researchers constructed an ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics that included different assumptions about immune decay, transmission heterogeneity, and access to treatment. Such models simulate the passage of thousands of hypothetical individuals through different stages of malaria infection; movement between stages occurs stochastically (by chance) at a probability based on field data. Each model was used to predict the health benefits over 14 years of RTS,S deployment through EPI (with and without catch-up vaccination for infants who were not immunized during their first three months of life), through EPI and supplementary vaccination of school children, and through mass vaccination campaigns every five years at malaria transmission levels of 2, 11, and 20 infectious bites per person per annum (low, medium, and high entomological inoculation rates [EIRs], respectively). The predicted benefits of EPI vaccination programs over the 14-year period were modest and similar over a wide range of settings. However, EPI with an initial catch-up phase averted the most deaths per vaccine dose at higher EIRs. At the lowest EIR, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose than other strategies, even at modest coverage.
What Do These Findings Mean?
The ensemble approach taken here suggests that targeted mass vaccination with RTS,S in low transmission settings may have greater health benefits than vaccination through national EPI programs. Importantly, this computer-intensive approach, which used computers made available over the internet by volunteers, provides more secure predictions than can be obtained using single models. In addition, it suggests that predictions made about the health effects of RTS,S vaccination for low transmission settings are more likely to be accurate than those made for higher transmission settings. However, this study only reports the first stages of using ensemble modeling to predict the health effects of RTS,S vaccination. Future studies will need to combine the outputs of multiple models with economic analyses to provide a rational basis for the design of vaccine-containing malaria control and elimination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001157.
Information is available from the World Health Organization on malaria and on malaria immunization; the 2010 World Malaria Report provides details on the current global malaria situation; WHO also provides information on its Expanded Programme on Immunization (EPI), and its Global Immunization Vision and Strategy (some information is available in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The latest results from the phase III trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
Wikipedia has a page on ensemble forecasting (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
OpenMalaria is the open source simulator of malaria epidemiology and control used in this study; BOINC is the open source software for volunteer computing and grid computing that was used to run the simulations
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001157
PMCID: PMC3260300  PMID: 22272189
6.  Parental Delay or Refusal of Vaccine Doses, Childhood Vaccination Coverage at 24 Months of Age, and the Health Belief Model 
Public Health Reports  2011;126(Suppl 2):135-146.
Objective
We evaluated the association between parents' beliefs about vaccines, their decision to delay or refuse vaccines for their children, and vaccination coverage of children at aged 24 months.
Methods
We used data from 11,206 parents of children aged 24–35 months at the time of the 2009 National Immunization Survey interview and determined their vaccination status at aged 24 months. Data included parents' reports of delay and/or refusal of vaccine doses, psychosocial factors suggested by the Health Belief Model, and provider-reported up-to-date vaccination status.
Results
In 2009, approximately 60.2% of parents with children aged 24–35 months neither delayed nor refused vaccines, 25.8% only delayed, 8.2% only refused, and 5.8% both delayed and refused vaccines. Compared with parents who neither delayed nor refused vaccines, parents who delayed and refused vaccines were significantly less likely to believe that vaccines are necessary to protect the health of children (70.1% vs. 96.2%), that their child might get a disease if they aren't vaccinated (71.0% vs. 90.0%), and that vaccines are safe (50.4% vs. 84.9%). Children of parents who delayed and refused also had significantly lower vaccination coverage for nine of the 10 recommended childhood vaccines including diphtheria-tetanus-acellular pertussis (65.3% vs. 85.2%), polio (76.9% vs. 93.8%), and measles-mumps-rubella (68.4% vs. 92.5%). After adjusting for sociodemographic differences, we found that parents who were less likely to agree that vaccines are necessary to protect the health of children, to believe that their child might get a disease if they aren't vaccinated, or to believe that vaccines are safe had significantly lower coverage for all 10 childhood vaccines.
Conclusions
Parents who delayed and refused vaccine doses were more likely to have vaccine safety concerns and perceive fewer benefits associated with vaccines. Guidelines published by the American Academy of Pediatrics may assist providers in responding to parents who may delay or refuse vaccines.
PMCID: PMC3113438  PMID: 21812176
7.  Vaccination of children with a live-attenuated, intranasal influenza vaccine – analysis and evaluation through a Health Technology Assessment 
Background: Influenza is a worldwide prevalent infectious disease of the respiratory tract annually causing high morbidity and mortality in Germany. Influenza is preventable by vaccination and this vaccination is so far recommended by the The German Standing Committee on Vaccination (STIKO) as a standard vaccination for people from the age of 60 onwards. Up to date a parenterally administered trivalent inactivated vaccine (TIV) has been in use almost exclusively. Since 2011 however a live-attenuated vaccine (LAIV) has been approved additionally. Consecutively, since 2013 the STIKO recommends LAIV (besides TIV) for children from 2 to 17 years of age, within the scope of vaccination by specified indications. LAIV should be preferred administered in children from 2 to 6 of age. The objective of this Health Technology Assessment (HTA) is to address various research issues regarding the vaccination of children with LAIV. The analysis was performed from a medical, epidemiological and health economic perspective, as well as from an ethical, social and legal point of view.
Method: An extensive systematic database research was performed to obtain relevant information. In addition a supplementary research by hand was done. Identified literature was screened in two passes by two independent reviewers using predefined inclusion and exclusion criteria. Included literature was evaluated in full-text using acknowledged standards. Studies were graded with the highest level of evidence (1++), if they met the criteria of European Medicines Agency (EMA)-Guidance: Points to consider on applications with 1. meta-analyses; 2. one pivotal study.
Results: For the medical section, the age of the study participants ranges from 6 months to 17 years. Regarding study efficacy, in children aged 6 months to ≤7 years, LAIV is superior to placebo as well as to a vac-cination with TIV (Relative Risk Reduction – RRR – of laboratory confirmed influenza infection approx. 80% and 50%, respectively). In children aged >7 to 17 years (= 18th year of their lives), LAIV is superior to a vaccination with TIV (RRR 32%). For this age group, no studies that compared LAIV with placebo were identified. It can be concluded that there is high evidence for superior efficacy of LAIV (compared to placebo or TIV) among children aged 6 months to ≤7 years. For children from >7 to 17 years, there is moderate evidence for superiority of LAIV for children with asthma, while direct evidence for children from the general population is lacking for this age group. Due to the efficacy of LAIV in children aged 6 months to ≤7 years (high evidence) and the efficacy of LAIV in children with asthma aged >7 to 17 years (moderate evidence), LAIV is also very likely to be efficacious among children in the general population aged >7 to 17 years (indirect evidence). In the included studies with children aged 2 to 17 years, LAIV was safe and well-tolerated; while in younger children LAIV may increase the risk of obstruction of the airways (e.g. wheezing).
In the majority of the evaluated epidemiological studies, LAIV proved to be effective in the prevention of influenza among children aged 2–17 years under everyday conditions (effectiveness). The trend appears to indicate that LAIV is more effective than TIV, although this can only be based on limited evidence for methodological reasons (observational studies). In addition to a direct protective effect for vaccinated children themselves, indirect protective ("herd protection") effects were reported among non-vaccinated elderly population groups, even at relatively low vaccination coverage of children. With regard to safety, LAIV generally can be considered equivalent to TIV. This also applies to the use among children with mild chronically obstructive conditions, from whom LAIV therefore does not have to be withheld. In all included epidemiological studies, there was some risk of bias identified, e.g. due to residual confounding or other methodology-related sources of error.
In the evaluated studies, both the vaccination of children with previous illnesses and the routine vaccination of (healthy) children frequently involve cost savings. This is especially the case if one includes indirect costs from a societal perspective. From a payer perspective, a routine vaccination of children is often regarded as a highly cost-effective intervention. However, not all of the studies arrive at consistent results. In isolated cases, relatively high levels of cost-effectiveness are reported that make it difficult to perform a conclusive assessment from an economic perspective. Based on the included studies, it is not possible to make a clear statement about the budget impact of using LAIV. None of the evaluated studies provides results for the context of the German healthcare setting.
The efficacy of the vaccine, physicians' recommendations, and a potential reduction in influenza symptoms appear to play a role in the vaccination decision taken by parents/custodians on behalf of their children. Major barriers to the utilization of influenza vaccination services are a low level of perception and an underestimation of the disease risk, reservations concerning the safety and efficacy of the vaccine, and potential side effects of the vaccine. For some of the parents surveyed, the question as to whether the vaccine is administered as an injection or nasal spray might also be important.
Conclusion: In children aged 2 to 17 years, the use of LAIV can lead to a reduction of the number of influenza cases and the associated burden of disease. In addition, indirect preventive effects may be expected, especially among elderly age groups. Currently there are no data available for the German healthcare setting. Long-term direct and indirect effectiveness and safety should be supported by surveillance programs with a broader use of LAIV.
Since there is no general model available for the German healthcare setting, statements concerning the cost-effectiveness can be made only with precaution. Beside this there is a need to conduct health eco-nomic studies to show the impact of influenza vaccination for children in Germany. Such studies should be based on a dynamic transmission model. Only these models are able to include the indirect protective effects of vaccination correctly.
With regard to ethical, social and legal aspects, physicians should discuss with parents the motivations for vaccinating their children and upcoming barriers in order to achieve broader vaccination coverage.
The present HTA provides an extensive basis for further scientific approaches and pending decisions relating to health policy.
doi:10.3205/hta000119
PMCID: PMC4219018  PMID: 25371764
Health Technology Assessment; HTA; LAIV; live attenuated vaccine; TIV; trivalent inactivated vaccine
8.  Measuring the Performance of Vaccination Programs Using Cross-Sectional Surveys: A Likelihood Framework and Retrospective Analysis 
PLoS Medicine  2011;8(10):e1001110.
Justin Lessler and colleagues describe a method that estimates the fraction of a population accessible to vaccination activities, and they apply it to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone.
Background
The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generally inconsistent with the proportion found to be vaccinated in Demographic and Health Surveys (DHS). We describe a method that estimates the fraction of the population accessible to vaccination activities, as well as within-campaign inefficiencies, thus providing a consistent estimate of vaccination coverage.
Methods and Findings
We developed a likelihood framework for estimating the effective coverage of vaccination programs using cross-sectional surveys of vaccine coverage combined with administrative data. We applied our method to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone, using data from each country's most recent DHS survey and administrative coverage data reported to the World Health Organization. We estimate that 93% (95% CI: 91, 94) of the population in Ghana was ever covered by any measles vaccination activity, 77% (95% CI: 78, 81) in Madagascar, and 69% (95% CI: 67, 70) in Sierra Leone. “Within-activity” inefficiencies were estimated to be low in Ghana, and higher in Sierra Leone and Madagascar. Our model successfully fits age-specific vaccination coverage levels seen in DHS data, which differ markedly from those predicted by naïve extrapolation from country-reported and World Health Organization–adjusted vaccination coverage.
Conclusions
Combining administrative data with survey data substantially improves estimates of vaccination coverage. Estimates of the inefficiency of past vaccination activities and the proportion not covered by any activity allow us to more accurately predict the results of future activities and provide insight into the ways in which vaccination programs are failing to meet their goals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Immunization (vaccination) is a proven, cost-effective tool for controlling life-threatening infectious diseases. It provides protection against infectious diseases by priming the human immune system to respond quickly and efficiently to bacteria, viruses, and other disease-causing organisms (pathogens). Whenever the human body is exposed to a pathogen, the immune system—a network of cells, tissues, and organs—mounts an attack against the foreign invader. Importantly, the immune system “learns” from the encounter, and the next time the body is exposed to the same pathogen, the immune system responds much faster to the threat. Immunization exposes the body to a very small amount of a pathogen, thereby safely providing protection against subsequent infection. More than two billion deaths are averted every year through routine childhood immunization and supplemental immunization activities (mass vaccination campaigns designed to increase vaccination coverage where immunization goals have not been reached by routine vaccination). Indeed, these two types of vaccination activities have eliminated smallpox from the world and are close to doing the same for several other infectious diseases.
Why Was This Study Done?
To reduce deaths from infectious diseases even further, it is important to know the proportion of the population reached by vaccination activities. At present, countries report vaccination coverage to the World Health Organization (WHO) that is calculated by dividing the number of vaccine doses delivered during the activity by the size of the target population. However, estimates arrived at through this “administrative method” do not account for vaccine doses that were not actually delivered, and can only reflect a single vaccination activity, which prevents us from identifying populations that may be systematically missed by all vaccination activities (for example, children living in remote areas, or children whose parents refuse vaccination). Moreover, estimates of coverage obtained by the administrative method rarely agree with estimates obtained through cross-sectional surveys such as Demographic and Health Surveys (DHS), which are household surveys of family circumstances and health undertaken at a single time point. In this study, the researchers developed a method for measuring the performance of vaccination activities that estimates the fraction of the population accessible to these activities and within-activity inefficiencies. They then tested their method by applying it to measles vaccination in three African countries; before 1980, measles killed about 2.6 million children worldwide every year, but vaccination activities have reduced this death toll to about 164,000 per year.
What Did the Researchers Do and Find?
The researchers developed a set of formulae (a “likelihood framework”) to estimate the effective coverage of vaccination activities using data on vaccine coverage from cross-sectional surveys and administrative data. They then applied their method to measles vaccination in Ghana, Madagascar, and Sierra Leone using data obtained in each country's most recent DHS survey and administrative data reported to WHO. The researchers estimate that 93%, 77%, and 65% of the target populations in Ghana, Madagascar, and Sierra Leone, respectively, were ever covered by any vaccination activity, and that inefficiencies within vaccination activities were low for Ghana, but higher for Madagascar and Sierra Leone. Consequently, the researchers' estimates of vaccination activity coverage were substantially lower than the administrative estimates for Madagascar and Sierra Leone but only slightly lower than that for Ghana. Finally, the researchers' estimates of routine vaccination coverage were generally lower than WHO-adjusted estimates but broadly agreed with age-specific vaccination coverage levels from DHS surveys.
What Do These Findings Mean?
Although the accuracy of the estimates provided by this likelihood framework depends on the assumptions included in the framework and the quality of the data fed into it, these findings show that, by combining administrative data with survey data, estimates of vaccine coverage can be substantially improved. By providing estimates of both the inefficiency of past vaccination activities and the proportion of the target population inaccessible to any vaccination activity, this method should help public health experts predict the results of future activities and help them understand why some vaccination programs fail to meet their goals. Importantly, knowing both the size of the inaccessible population and the inefficiency level of past programs makes it possible to estimate the effect of providing additional doses of vaccine on vaccination coverage. Finally, the application of this new method might help individual countries understand how susceptibility to specific infectious diseases is building up in their population and enable them to avoid outbreaks similar to the measles outbreaks that have recently occurred in several African countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001080.
WHO provides information about immunization and details of its Expanded Program on Immunization and its Global Immunization Vision and Strategy; WHO Africa provides details about measles immunization in Africa; a photo story about mass measles vaccination in Côte d’Ivoire is available (some material in several languages)
The UK National Health Service Choices website provides information for members of the public about immunization
The Measles Initiative is a collaborative effort that aims to reduce global measles mortality through mass vaccination campaigns and by strengthening routine immunization; its website includes information on measles and measles vaccination, including photos and videos of vaccination activities
MedlinePlus provides links to additional resources about immunization and about measles (in English and Spanish)
The charity website Healthtalkonline has interviews with UK parents about their experience of immunizing their children
doi:10.1371/journal.pmed.1001110
PMCID: PMC3201935  PMID: 22039353
9.  Parental information-seeking behaviour in childhood vaccinations 
BMC Public Health  2013;13:1219.
Background
People want to be well informed and ask for more information regarding their health. The public can use different sources (i.e. the Internet, health care providers, friends, family, television, radio, and newspapers) to access information about their health. Insight into the types and sources of vaccine related information that parents use, and reasons why they seek extra information is needed to improve the existing information supply about childhood vaccinations.
Methods
Dutch parents with one or more children aged 0–4 years received an online questionnaire (N = 4000) measuring psychosocial determinants of information-seeking behaviour and self-reports of types and sources of vaccine information searched for (response rate 14.8%). We also tested two invitation approaches (i.e., reply card versus Internet link in invitation letter) to observe the difference in response rate.
Results
Almost half of the parents (45.8%) searched for extra information. Of all the respondents, 13% indicated they had missed some information, particularly about side effects of vaccines (25%). Intention to search for vaccination information was influenced by positive attitude and perceived social norm towards information-seeking behaviour. There was no difference in the response rate between the two invitation approaches.
Conclusions
The information provided by the National Immunization Programme (NIP) might be sufficient for most parents. However, some parents mentioned that they did not receive enough information about side effects of vaccinations, which was also the topic most searched for by parents. Public Health Institutes (PHIs) and child healthcare workers should therefore be aware of the importance to mention this aspect in their communication (materials) towards parents. The PHIs must ensure that their website is easy to find with different search strategies. Since the child healthcare worker is perceived as the most reliable information source, they should be aware of their role in educating parents about the NIP.
doi:10.1186/1471-2458-13-1219
PMCID: PMC3909325  PMID: 24358990
Information seeking; Information need; Internet; Reasoned action approach; Health communication; Vaccination
10.  Vaccine Criticism on the World Wide Web 
Background
The incidence of vaccine-preventable diseases is directly related to the number of unvaccinated children. Parents who refuse vaccination of their children frequently express concerns about vaccine safety. The Internet can influence perceptions about vaccines because it is the fastest growing source of consumer health information. However, few studies have analyzed vaccine criticism on the Web.
Objective
The purposes of this paper are to examine vaccine criticism on the Internet and to analyze the websites in order to identify common characteristics and ethical allegations.
Methods
A structured Web search was conducted for the terms “vaccine,” “vaccination,” “vaccinate,” and “anti-vaccination” using a metasearch program that incorporated 8 search engines. This yielded 1138 Web pages representing 750 sites. Two researchers reviewed the sites for inclusion/exclusion criteria, resulting in 78 vaccine-critical sites, which were then abstracted for design, content, and allegations.
Results
The most common characteristic of vaccine-critical websites was the inclusion of statements linking vaccinations with specific adverse reactions, especially idiopathic chronic diseases such as multiple sclerosis, autism, and diabetes. Other common attributes (≥ 70% of websites) were links to other vaccine-critical websites; charges that vaccines contain contaminants, mercury, or “hot lots” that cause adverse events; claims that vaccines provide only temporary protection and that the diseases prevented are mild; appeals for responsible parenting through education and resisting the establishment; allegations of conspiracies and cover-ups to hide the truth about vaccine safety; and charges that civil liberties are violated through mandatory vaccination.
Conclusions
Vaccine-critical websites frequently make serious allegations. With the burgeoning of the Internet as a health information source, an undiscerning or incompletely educated public may accept these claims and refuse vaccination of their children. As this occurs, the incidence of vaccine-preventable diseases can be expected to rise.
doi:10.2196/jmir.7.2.e17
PMCID: PMC1550643  PMID: 15998608
Vaccines; Internet; immunization; vaccine safety; vaccine criticism; anti-vaccine
11.  Reasons for non-vaccination in pediatric patients visiting tertiary care centers in a polio-prone country 
Archives of Public Health  2013;71(1):19.
Background
The Expanded Program on Immunization (EPI) was initiated by World Health Organization (WHO) in 1974 in order to save children from life threatening, disabling vaccine-preventable diseases (VPDs). In Pakistan, this program was launched in 1978 with the main objectives of eradicating polio by 2012, eliminating measles and neonatal tetanus by 2015, and minimizing the incidence of other VPDs. However, despite the efforts of government and WHO, this program has not received the amount of success that was desired. Hence, the objectives of this study were to elucidate the main reasons behind not achieving the full immunization coverage in Pakistan, the awareness of children’s attendant about the importance of vaccination, their attitudes, thoughts and fears regarding childhood immunization, and the major hurdles faced in pursuit of getting their children vaccinated.
Methods
This was an observational, cross-sectional, questionnaire-based study conducted during a one year period from 4th January, 2012 to 6th January, 2013 at the pediatric outpatient clinics of Civil Hospital (CHK) and National Institute of Child Health (NICH). We attempted to interview all the parents who could be approached during the period of the study. Thus, convenience sampling was employed. The parents were approached in the clinics and interviewed after seeking informed, written consent. Those patients who were not accompanied by either of their parents were excluded from the study. The study instrument comprised of three sections. The first section consisted was concerned with the demographics of the patient and the parents. The second section dealt with the reasons for complete vaccination or under-vaccination. The last section aimed to assess the knowledge, attitudes and beliefs of the respondents.
Results
Out of 1044 patients, only 713(68.3%) were fully vaccinated, 239(22.9%) were partially vaccinated while 92(8.8%) had never been vaccinated. The vaccination status showed statistically significant association with ethnicity, income, residence, number of children and paternal occupation (p < 0.05 for all). The most common provocative factor for vaccination compliance was mass media (61.9%). The most common primary reason for non-vaccination was lack of knowledge (18.1%), whereas the most common secondary reason for non-vaccination was religious taboos (31.4%). Majority of the respondents demonstrated poor knowledge of EPI schedules or VPDs. However, most believed that there was a need for more active government/NGO involvement in this area.
Conclusion
The most common primary reason for non-vaccination, i.e. lack of knowledge, and the most common secondary reason, i.e. religious taboos, imply that there is dire need to promote awareness among the masses in collaboration with NGOs, and major religious and social organizations.
doi:10.1186/0778-7367-71-19
PMCID: PMC3716633  PMID: 23848348
12.  Frequency of Adverse Events after Vaccination with Different Vaccinia Strains 
PLoS Medicine  2006;3(8):e272.
Background
Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.
Methods and Findings
We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0–6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0–31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.
Conclusions
Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
Analysis of historical data for adverse events suggests that the commonly assumed number of one death per million vaccinations is inaccurate. Large differences between different vaccinia strains used should be taken into account when mass vaccinations are considered.
Editors' Summary
Background.
For thousands of years, smallpox was one of the world's most-feared diseases. This contagious disease, caused by the variola virus, historically killed about 30 percent of the people it infected. Over the centuries, it probably killed more people than all other infectious diseases combined, but it was also the first disease to be prevented by vaccination. In 1796, the English physician Edward Jenner rubbed pus from the spots of a milkmaid with cowpox into scratches on a young boy's arm; according to folklore, people who caught cowpox, a related but mild disease of cows, were protected against smallpox. Six weeks later, after a mild bout of cowpox, when the boy was challenged with pus from a smallpox patient, he did not develop smallpox. This vaccination procedure was later refined so that people were inoculated with pure preparations of live vaccinia virus, which is closely related to the smallpox and cowpox viruses, and by 1979 a global vaccination campaign had totally eradicated the disease.
Why Was This Study Done?
Smallpox vaccination has some adverse effects. In particular, vaccinia virus occasionally infects the brain. This so-called post-vaccination encephalitis can cause permanent brain damage and, it has been estimated, kills one vaccinee in every million. Consequently, as smallpox became rarer, the dangers of vaccination began to outweigh its benefits. Routine smallpox vaccination stopped in the US in 1972, and in 1980 the World Health Organization recommended that all countries stop vaccination. Now, however, there are fears that smallpox may be used for bioterrorism. If this did happen, exposed individuals and their contacts, possibly even whole populations, would have to be vaccinated as quickly as possible (very few people now have strong immunity to smallpox). Many countries have stockpiles of smallpox vaccines for this eventuality, but these contain different vaccinia virus strains. In this study, the researchers examined historical data to discover whether these strains differ in their potential to cause encephalitis and death. This information should help public-health officials plan their vaccination strategies in response to a bioterrorism attack with smallpox.
What Did the Researchers Do and Find?
The researchers collected data from published studies on smallpox vaccination and adverse events from several countries from the late 1950s onwards. They then used these data to extrapolate how often the different vaccinia strains might cause encephalitis and death if they were used today in vaccination programs. They estimate that vaccinating with the New York City Board of Health (NYCBH) strain, which is stockpiled in the US, might cause 2.9 cases of post-vaccination encephalitis and 1.4 deaths per million vaccinated individuals. In contrast, the Lister strain, which is stockpiled in many European countries, might cause 26.2 cases of post-vaccination encephalitis and 2.5 deaths per million vaccinees. For both strains, vaccination of children younger than 1 year old would cause the highest death rate, and individuals being re-vaccinated would be less likely to die than those being vaccinated for the first time. Finally, the researchers use their figures to estimate that about ten people would die if mass vaccination with the NYCBH strain were used in the Netherlands (population 16 million), whereas 55 people would die if the Lister strain were used.
What Do These Findings Mean?
The data used in this study are of variable quality, so the figures calculated by the researchers are only estimates. For instance, given the scatter of the original data, mass vaccination in the Netherlands with the Lister strain might cause anywhere between seven and nearly 200 deaths. However, the study clearly suggests that more serious adverse events would occur after vaccination with the Lister strain than after vaccination with the NYCBH strain. It also indicates that even in the US, where the NYCBH vaccine strain is stockpiled, previous analyses of the effects of vaccination in response to a bioterrorist attack have probably underestimated how many people might die from post-vaccination encephalitis. Public-health decision makers should incorporate these new estimates into their planning for a smallpox outbreak. These increased estimates of adverse events after vaccination might, for example, make mass vaccination with the Lister strain of vaccinia virus less acceptable. Instead, public-health officials might decide to rely on vaccination of only the people directly exposed to released smallpox virus and their close contacts (ring vaccination) to contain a smallpox outbreak.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030272.
World Health Organization, information on smallpox and preparedness in the event of a smallpox outbreak
MedlinePlus encyclopedia entry on smallpox
US National Institute of Allergy and Infectious Diseases, patient fact sheet on smallpox
US Centers for Disease Control and Prevention, information for patients and professionals on smallpox
Wikipedia page on smallpox (note that Wikipedia is a free online encyclopedia that anyone can edit)
Wellcome Library MedHist, links to information on the history of smallpox vaccination
doi:10.1371/journal.pmed.0030272
PMCID: PMC1551910  PMID: 16933957
13.  Parents Seeking Health-Related Information on the Internet: Cross-Sectional Study 
Background
The Internet represents an increasingly common source of health-related information, and it has facilitated a wide range of interactions between people and the health care delivery system.
Objective
To establish the extent of Internet access and use to gather information about health topics and the potential implications to health care among the adult population in Calabria region, Italy.
Methods
This cross-sectional study was conducted from April to June 2012. The sample consisted of 1544 adults aged ≥18 years selected among parents of public school students in the geographic area of Catanzaro in southern Italy. A 2-stage sample design was planned. A letter summarizing the purpose of the study, an informed consent form, and a questionnaire were given to selected student to deliver to their parents. The final survey was formulated in 5 sections: (1) sociodemographic characteristics, (2) information about chronic diseases and main sources of health care information, (3) information about Internet use, (4) data about the effects of using the Internet to search for health information, and (5) knowledge and use of social networks.
Results
A total of 1039 parents completed the questionnaire, with a response rate equivalent to 67.29%. Regarding health-related information types, 84.7% of respondents used the Internet to search for their own medical conditions or those of family members or relatives, 40.7% of parents reported looking for diet, body weight, or physical activity information, 29.6% searched for vaccines, 28.5% for screening programs, and 16.5% for smoking cessation tools and products. The results of the multiple logistic regression analysis showed that parents who looked for health-related information on the Internet were more likely to be female (OR 1.53, 95% CI 1.05-2.25), with a high school diploma (OR 1.69, 95% CI 1.02-2.81) or college degree (OR 2.14, 95% CI 1.21-3.78), younger aged (OR 0.96, 95% CI 0.94-0.99), with chronic conditions (OR 1.94, 95% CI 1.17-3.19), not satisfied with their general practitioner’s health-related information (OR 0.6, 95% CI 0.38-0.97), but satisfied with information from scientific journals (OR 1.99, 95% CI 1.33-2.98).
Conclusions
Our analyses provide important insights into Internet use and health information–seeking behaviors of the Italian population and contribute to the evidence base for health communication planning. Health and public health professionals should educate the public about acquiring health information online and how to critically appraise it, and provide tools to navigate to the highest-quality information. The challenge to public health practice is to facilitate the health-promoting use of the Web among consumers in conjunction with their health care providers.
doi:10.2196/jmir.2752
PMCID: PMC3785974  PMID: 24047937
adult; consumer health information; cross-sectional studies; health survey; Internet; Italy; questionnaires
14.  Vaccine beliefs of parents who oppose compulsory vaccination. 
Public Health Reports  2005;120(3):252-258.
OBJECTIVES: Our objectives were the following: (1) to describe the sociodemographic factors, vaccine beliefs, and behaviors that are associated with parental opposition to compulsory vaccination, and (2) to determine if the availability of a philosophical exemption in a parent's state of residence is associated with parental opposition to compulsory vaccination. METHODS: Data from the 2002 HealthStyles survey were analyzed. Chi-square analysis was used to identify significant associations between belief and behavior questions and opposition to compulsory vaccination for school entry. Multivariate logistic regression was conducted using significant variables from the bivariate analysis to identify independent predictors of opposition to compulsory vaccination among surveyed parents. RESULTS: Of respondents with at least one child aged < or = 18 years living in the household (n=1,527), 12% were opposed to compulsory vaccination. Survey results indicate that a parent's belief regarding compulsory vaccination for school entry is significantly associated with beliefs in the safety and utility of vaccines, as well as intention to have the youngest child fully vaccinated. Residence in a state that permits philosophical exemption to vaccination also was significantly associated with a parent's opposition to compulsory vaccination for school entry. CONCLUSIONS: Providing basic information to parents regarding vaccines and vaccine-preventable diseases may help reduce opposition to compulsory vaccination by reinforcing the safety and importance of routine childhood vaccinations.
PMCID: PMC1497722  PMID: 16134564
15.  Exploring reasons for non-vaccination against human papillomavirus in Italy 
BMC Infectious Diseases  2014;14(1):545.
Background
In Italy, free-of-charge HPV vaccination is offered to 11-year-old girls since 2007. The National Immunization Plan established the target coverage at a minimum of 70%; it should increase to 95% within 3-year time frame. In 2012, four year after the introduction of HPV vaccination, coverage was stable at 69%. We conducted a national cross-sectional study to explore barriers to vaccination in Italy.
Methods
Vaccination services selected, through the immunization registries, a sample of unvaccinated girls born in 1997 or 1998 and posted to their families a 23-items questionnaire inquiring barriers to vaccination, HPV knowledge, source of information on HPV, perception of risk of contracting HPV, advice from consulted health professionals on HPV vaccination.
Results
We analysed 1,738 questionnaires. Main barriers were fear of adverse events (reported by 80% of families), lack of trust in a new vaccine (76%), discordant information received by health professionals (65%) and scarce information on HPV vaccination (54%). Overall, 54% of families replied correctly to more than half of 10 questions exploring knowledge on HPV vaccination. Families with a high knowledge score were more likely to live in Northern and Central Italy, be Italian, have a high educational level, include a mother who attended cervical screening regularly and consult more information sources. Although paediatricians/general practitioners and gynaecologists were considered the most trusted source of information by 79% and 61% of respondents, they were consulted only by 49% and 31%. Among parents who discussed vaccination with a physician, 28% received discordant advices and 31% received the recommendation of accepting vaccination.
Conclusions
Fear of adverse events, discordance of information and advices from physicians, and scarce information were the more commonly reported barriers to HPV vaccination. Health professionals played a key role as information providers, thus they must be better trained to provide clear notions. Training needs to include the development of communication skills; transparent discussion about the pros and cons of vaccination may reduce fear of adverse events and increase trust in vaccination. The creation of a public health network around vaccination would allow sharing information and attitudes on vaccinations, so that homogeneous messages could reach the target population.
doi:10.1186/s12879-014-0545-9
PMCID: PMC4233085  PMID: 25410754
Human papillomavirus infection; Vaccines and immunisation; Uterine cervical cancer; Immunisation programs; Reasons for non-vaccination; Acceptance
16.  Risk Factors for Death among Children Less than 5 Years Old Hospitalized with Diarrhea in Rural Western Kenya, 2005–2007: A Cohort Study 
PLoS Medicine  2012;9(7):e1001256.
A hospital-based surveillance study conducted by Ciara O'Reilly and colleagues describes the risk factors for death amongst children who have been hospitalized with diarrhea in rural Kenya.
Background
Diarrhea is a leading cause of childhood morbidity and mortality in sub-Saharan Africa. Data on risk factors for mortality are limited. We conducted hospital-based surveillance to characterize the etiology of diarrhea and identify risk factors for death among children hospitalized with diarrhea in rural western Kenya.
Methods and Findings
We enrolled all children <5 years old, hospitalized with diarrhea (≥3 loose stools in 24 hours) at two district hospitals in Nyanza Province, western Kenya. Clinical and demographic information was collected. Stool specimens were tested for bacterial and viral pathogens. Bivariate and multivariable logistic regression analyses were carried out to identify risk factors for death. From May 23, 2005 to May 22, 2007, 1,146 children <5 years old were enrolled; 107 (9%) children died during hospitalization. Nontyphoidal Salmonella were identified in 10% (118), Campylobacter in 5% (57), and Shigella in 4% (42) of 1,137 stool samples; rotavirus was detected in 19% (196) of 1,021 stool samples. Among stools from children who died, nontyphoidal Salmonella were detected in 22%, Shigella in 11%, rotavirus in 9%, Campylobacter in 5%, and S. Typhi in <1%. In multivariable analysis, infants who died were more likely to have nontyphoidal Salmonella (adjusted odds ratio [aOR] = 6·8; 95% CI 3·1–14·9), and children <5 years to have Shigella (aOR = 5·5; 95% CI 2·2–14·0) identified than children who survived. Children who died were less likely to be infected with rotavirus (OR = 0·4; 95% CI 0·2–0·8). Further risk factors for death included being malnourished (aOR = 4·2; 95% CI 2·1–8·7); having oral thrush on physical exam (aOR = 2·3; 95% CI 1·4–3·8); having previously sought care at a hospital for the illness (aOR = 2·2; 95% CI 1·2–3·8); and being dehydrated as diagnosed at discharge/death (aOR = 2·5; 95% CI 1·5–4·1). A clinical diagnosis of malaria, and malaria parasites seen on blood smear, were not associated with increased risk of death. This study only captured in-hospital childhood deaths, and likely missed a substantial number of additional deaths that occurred at home.
Conclusion
Nontyphoidal Salmonella and Shigella are associated with mortality among rural Kenyan children with diarrhea who access a hospital. Improved prevention and treatment of diarrheal disease is necessary. Enhanced surveillance and simplified laboratory diagnostics in Africa may assist clinicians in appropriately treating potentially fatal diarrheal illness.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrhea—passing three or more loose or liquid stools per day—kills about 1.5 million young children every year, mainly in low- and middle-income countries. Globally, it is the second leading cause of death in under-5-year olds, causing nearly one in five child deaths. Diarrhea, which can lead to life-threatening dehydration, is a common symptom of gastrointestinal infections. The pathogens (viruses, bacteria, and parasites) that cause diarrhea spread through contaminated food or drinking water, and from person to person through poor hygiene and inadequate sanitation (unsafe disposal of human excreta). Interventions that prevent diarrhea include improvements in water supplies, sanitation and hygiene, the promotion of breast feeding, and vaccination against rotavirus (a major viral cause of diarrhea). Treatments for diarrhea include oral rehydration salts, which prevent and treat dehydration, zinc supplementation, which decreases the severity and duration of diarrhea, and the use of appropriate antibiotics when indicated for severe bacterial diarrhea.
Why Was This Study Done?
Nearly half of deaths from diarrhea among young children occur in Africa where diarrhea is the single largest cause of death among under 5-year-olds and a major cause of childhood illness. Unfortunately, although some of the risk factors for death from diarrhea in children in sub-Saharan Africa have been identified (for example, having other illnesses, poor nutrition, and not being breastfed), little is known about the relative contributions of different diarrhea-causing pathogens to diarrheal deaths. Clinicians need to know which of these pathogens are most likely to cause death in children so that they can manage their patients appropriately. In this cohort study, the researchers characterize the causes and risk factors associated with death among young children hospitalized for diarrhea in Nyanza Province, western Kenya, an area where most households have no access to safe drinking water and a quarter lack latrines. In a cohort study, a group of people with a specific condition is observed to identify which factors lead to different outcomes.
What Did the Researchers Do and Find?
The researchers enrolled all the children under 5 years old who were hospitalized over a two-year period for diarrhea at two district hospitals in Nyanza Province, tested their stool samples for diarrhea-causing viral and bacterial pathogens, and recorded which patients died in-hospital. They then used multivariable regression analysis (a statistical method) to determine which risk factors and diarrheal pathogens were associated with death among the children. During the study, 1,146 children were hospitalized, 107 of whom died in the hospital. 10% of all the stool samples contained nontyphoidal Salmonella, 4% contained Shigella (two types of diarrhea-causing bacteria), and 19% contained rotavirus. By contrast, 22% of the samples taken from children who died contained nontyphoidal Salmonella, 11% contained Shigella, 9% contained rotavirus, and 5% contained Campylobacter (another bacterial pathogen that causes diarrhea). Compared to survivors, infants (children under 1 year of age) who died were nearly seven times more likely to have nontyphoidal Salmonella in their stools and children under 5 years old who died were five and half times more likely to have Shigella in their stools but less likely to have rotavirus in their stools. Other factors associated with death included being malnourished, having oral thrush (a fungal infection of the mouth), having previously sought hospital care for diarrhea, and being dehydrated.
What Do These Findings Mean?
These findings indicate that, among young children admitted to the hospital in western Kenya with diarrhea, infections with nontyphoidal Salmonella and with Shigella (but not with rotavirus) were associated with an increased risk of death. Because this study only captured deaths in hospital and most diarrheal deaths in developing countries occur at home, these results may not accurately reflect the pathogens associated with overall childhood diarrheal deaths. In addition, they may not be generalizable to other geographical regions. Nevertheless, given that that there are currently no vaccines available for most bacterial diarrheal diseases, these findings highlight the importance of Kenya and other developing countries implementing effective strategies for the prevention and management of diarrheal diseases in children such as increasing access to improved water, sanitation, and hygiene, and community-level promotion of the use of oral rehydration solution and zinc supplements. They also suggest that enhanced surveillance and simplified laboratory diagnostics for diarrheal pathogens could help clinicians identify those children presenting to hospital with diarrhea who are at high risk of death and prioritize their treatment.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001256.
The World Health Organization provides information on diarrhea (in several languages); its 2009 report with UNICEF Diarrhea: why children are still dying and what can be done, which includes the WHO/UNICEF recommendations for the treatment and prevention of diarrhea in children, can be downloaded from the Internet
The children's charity UNICEF, which protects the rights of children and young people around the world, provides information on diarrhea (in several languages)
doi:10.1371/journal.pmed.1001256
PMCID: PMC3389023  PMID: 22802736
17.  Parental intention to have daughters receive the human papillomavirus vaccine 
Background
Concerns have been raised that parents may be reluctant to have their daughters receive the human papillomavirus (HPV) vaccine, because of a belief that doing so might be interpreted as condoning earlier and more frequent sexual activity. We determined intentions regarding vaccination among Canadian parents and factors that predicted parental intention to have their daughters vaccinated against HPV.
Methods
Parents of children 8–18 years of age, recruited from across Canada, were asked to respond to questions in the context of a grade 6, publicly funded, school-based HPV vaccine program. We performed backward logistic regression analysis to identify factors predictive of parents' intention to have their daughters vaccinated against HPV.
Results
Of the 1350 respondents with female children, more than 70% (73.8%; 95% confidence interval [CI] 71.5%– 76.1%) intended to have their daughters undergo vaccination against HPV. In multivariable modelling, parents who had positive attitudes toward vaccines (odds ratio [OR] 9.9, 95% CI 4.7–21.1), those who were influenced by subjective norms (OR 9.2, 95% CI 6.6–12.9), those who felt that the vaccine had limited influence on sexual behaviour (OR 3.2, 95% CI 2.2–4.6) and those who thought someone they knew was likely to get cervical cancer (OR 1.5, 95% CI 1.1–2.1) were more likely to intend that their daughters receive the HPV vaccine. Parents who were older (v. younger) (OR 0.6, 95% CI 0.4–0.8) and those who resided in British Columbia or Yukon Territory (v. Atlantic Canada) (OR 0.5, 95% CI 0.3–0.9) were less likely to intend that their daughters receive the HPV vaccine.
Interpretation
Most of the parents surveyed intended that their daughters would receive vaccination against HPV. Overall attitudes toward vaccines in general and toward the HPV vaccine in particular constituted the most significant predictor of parental intention with regard to vaccination.
doi:10.1503/cmaj.071022
PMCID: PMC2096481  PMID: 18056599
18.  Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants  
PLoS Medicine  2006;3(12):e525.
Background
In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the etiological agent of severe acute respiratory syndrome, a disease characterized by severe pneumonia that sometimes results in death. SARS-CoV is a zoonotic virus that crossed the species barrier, most likely originating from bats or from other species including civets, raccoon dogs, domestic cats, swine, and rodents. A SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. We report the comprehensive investigation of SARS vaccine efficacy in young and senescent mice following homologous and heterologous challenge.
Methods and Findings
Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N), we demonstrate that VRP-S, but not VRP-N vaccines provide complete short- and long-term protection against homologous strain challenge in young and senescent mice. To test VRP vaccine efficacy against a heterologous SARS-CoV, we used phylogenetic analyses, synthetic biology, and reverse genetics to construct a chimeric virus (icGDO3-S) encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV. icGD03-S replicated efficiently in human airway epithelial cells and in the lungs of young and senescent mice, and was highly resistant to neutralization with antisera directed against the Urbani strain. Although VRP-S vaccines provided complete short-term protection against heterologous icGD03-S challenge in young mice, only limited protection was seen in vaccinated senescent animals. VRP-N vaccines not only failed to protect from homologous or heterologous challenge, but resulted in enhanced immunopathology with eosinophilic infiltrates within the lungs of SARS-CoV–challenged mice. VRP-N–induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses.
Conclusions
This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.
Experiments in mice suggest challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations.
Editors' Summary
Background.
Severe acute respiratory syndrome (SARS) is a flu-like illness and was first recognized in China in 2002, after which the disease rapidly spread around the world. SARS was associated with high death rates, much higher than those for flu. Around 10% of people recognized as being infected with SARS died, and the death rate approached 50% among elderly people. The virus causing SARS was identified as a member of the coronavirus family; it is generally thought that this virus “jumped” to humans from bats, which harbor related viruses. Although SARS was declared eradicated by the World Health Organization in May 2005, there is still the possibility that similar viruses will again cross the species barrier and infect humans, with potentially serious consequences. As a result, many groups are working to develop vaccines that will protect against SARS infection.
Why Was This Study Done?
A SARS vaccine should be effective in people of all ages, including the elderly who are more likely to get seriously ill or die if they become infected. In addition, potential vaccines should protect against different variants of the virus, because there are different types of the virus that could potentially cross the species barrier from animals to humans. Of the different proteins that make up the SARS coronavirus, the spike glycoprotein is thought to elicit an immune response in humans that can protect against future infection. The researchers therefore examined vaccine candidates based on this particular protein (termed SARS-CoV S), as well as a second one called SARS-CoV N, in mice. Specifically, they tested whether the vaccines would protect against SARS infection in both young and older mice, and whether they would protect against infection by different strains of the SARS virus.
What Did the Researchers Do and Find?
The researchers created vaccines based on SARS-CoV S and SARS-CoV N by taking the genes coding for those proteins and inserting them into another type of virus particle that acted as a delivery vehicle. They injected mice with these vaccines and then tested whether the mice generated an immune response against the specific SARS proteins, which they did. The next step was to work out whether mice injected with the vaccines would be protected against later infection with SARS-CoV. The researchers found that mice injected with vaccine based on SARS-CoV S were protected against later infection with a standard SARS-CoV strain, both in the short term (eight weeks after vaccination) and the long term (54 weeks after vaccination). However, the vaccine based on SARS-CoV N did not seem to result in protection, and, worryingly, caused pathological changes in the lungs of mice following virus challenge. To find out if their candidate vaccines would protect against different strains of SARS, the researchers made a synthetic test virus that contained a mixture of genetic material from different natural variants of the virus. This test virus was used to “challenge” mice that had been immunized with the two different vaccines. The researchers found that the vaccine based on SARS-CoV S protected against infection by the test virus when mice were vaccinated young, but it failed to efficiently protect when administered to older mice.
What Do These Findings Mean?
The findings confirm others suggesting that vaccines based on the SARS-CoV S protein are more effective than those based on SARS-CoV N. They also suggest that the former can provide long-term protection in animals vaccinated young against closely related viruses. However, protection against more distantly related viruses remains a challenge, especially when vaccinating older animals. The differences seen between young and older mice suggest that older mice might provide a useful model for animal testing of candidate vaccines for diseases like SARS, flu, and West Nile virus that pose a particular threat to elderly people. Overall, these results provide useful lessons toward future SARS vaccine development in animals. The synthetic virus strain generated here, and others like it, are likely to be useful tools for such future studies.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030525.
• The World Health Organization provides guidance, archives, and other information resources on SARS
• Information from the US Centers for Disease Control on SARS
• Wikipedia (an internet encyclopedia anyone can edit) has an entry on SARS
• Collected resources from MedLinePlus about SARS
doi:10.1371/journal.pmed.0030525
PMCID: PMC1716185  PMID: 17194199
19.  Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study 
PLoS Medicine  2011;8(1):e1000388.
Results from a European multicentre case-control study reported by Marta Valenciano and colleagues suggest good protection by the pandemic monovalent H1N1 vaccine against pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine on H1N1.
Background
A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1).
Methods and Findings
Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9).
Conclusions
Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Following the World Health Organization's declaration of pandemic phase six in June 2009, manufacturers developed vaccines against pandemic influenza A 2009 (pH1N1). On the basis of the scientific opinion of the European Medicines Agency, the European Commission initially granted marketing authorization to three pandemic vaccines for use in European countries. During the autumn of 2009, most European countries included the 2009–2010 seasonal influenza vaccine and the pandemic vaccine in their influenza vaccination programs.
The Influenza Monitoring Vaccine Effectiveness in Europe network (established to monitor seasonal and pandemic influenza vaccine effectiveness) conducted seven case-control and three cohort studies in seven European countries in 2009–2010 to estimate the effectiveness of the pandemic and seasonal vaccines. Data from the seven pilot case-control studies were pooled to provide overall adjusted estimates of vaccine effectiveness.
Why Was This Study Done?
After seasonal and pandemic vaccines are made available to populations, it is necessary to estimate the effectiveness of the vaccines at the population level during every influenza season. Therefore, this study was conducted in European countries to estimate the pandemic influenza vaccine effectiveness and seasonal influenza vaccine effectiveness against people presenting to their doctor with influenza-like illness who were confirmed (by laboratory tests) to be infected with pH1N1.
What Did the Researchers Do and Find?
The researchers conducted a multicenter case-control study on the basis of practitioner surveillance networks from seven countries—France, Hungary, Ireland, Italy, Romania, Portugal, and Spain. Patients consulting a participating practitioner for influenza-like illness had a nasal or throat swab taken within 8 days of symptom onset. Cases were swabbed patients who tested positive for pH1N1. Patients presenting with influenza-like illness whose swab tested negative for any influenza virus were controls.
Individuals were considered vaccinated if they had received a dose of the vaccine more than 14 days before the date of onset of influenza-like illness and unvaccinated if they were not vaccinated at all, or if the vaccine was given less than 15 days before the onset of symptoms. The researchers analyzed pandemic influenza vaccination effectiveness in those vaccinated less than 8 days, those vaccinated between and including 8 and 14 days, and those vaccinated more than 14 days before onset of symptoms compared to those who had never been vaccinated.
The researchers used modeling (taking account of all potential confounding factors) to estimate adjusted vaccine effectiveness and stratified the adjusted pandemic influenza vaccine effectiveness and the adjusted seasonal influenza vaccine effectiveness in three age groups (<15, 15–64, and ≥65 years of age).
The adjusted results suggest that the 2009–2010 seasonal influenza vaccine did not protect against pH1N1 illness. However, one dose of the pandemic vaccines used in the participating countries conferred good protection (65.5%–100% according to various stratifications performed) against pH1N1 in people who attended their practitioner with influenza-like illness, especially in people aged <65 years and in those without any chronic disease. Furthermore, good pandemic influenza vaccine effectiveness was observed as early as 8 days after vaccination.
What Do These Findings Mean?
The results of this study provide early estimates of the pandemic influenza vaccine effectiveness suggesting that the monovalent pandemic vaccines have been effective. The findings also give an indication of the vaccine effectiveness for the Influenza A (H1N1) 2009 strain included in the 2010–2011 seasonal vaccines, although specific vaccine effectiveness studies will have to be conducted to verify if similar good effectiveness are observed with 2010–2011 trivalent vaccines. However, the results of this study should be interpreted with caution because of limitations in the pandemic context (late timing of the studies, low incidence, low vaccine coverage leading to imprecise estimates) and potential biases due the study design, confounding factors, and missing values. The researchers recommend that in future season studies, the sample size per country should be enlarged in order to allow for precise pooled and stratified analyses.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000388.
The World Health Organization has information on H1N1 vaccination
The US Centers for Disease Control and Prevention provides a fact sheet on the 2009 H1N1 influenza virus
The US Department of Health and Human services has a comprehensive website on flu
The European Centre for Disease Prevention and Control provides information on 2009 H1N1 pandemic
The European Centre for Disease Prevention and Control presents a summary of the 2009 H1N1 pandemic in Europe and elsewhere
doi:10.1371/journal.pmed.1000388
PMCID: PMC3019108  PMID: 21379316
20.  Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis 
PLoS Medicine  2010;7(3):e1000249.
Jessica Shearer and colleagues analyze data from 147 countries to identify factors that influence the time taken to introduce routine vaccination against Haemophilus influenzae type b (Hib).
Background
Adoption of new and underutilized vaccines by national immunization programs is an essential step towards reducing child mortality. Policy decisions to adopt new vaccines in high mortality countries often lag behind decisions in high-income countries. Using the case of Haemophilus influenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis of country-level economic, epidemiological, programmatic and policy-related factors, as well as the role of the Global Alliance for Vaccines and Immunisation (GAVI Alliance).
Methods and Findings
Data for 147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors that are associated with the time to decision to adopt Hib vaccine. In multivariable models that control for Gross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the time to decision by a factor of 0.37 (95% CI 0.18–0.76), or 63%. The presence of two or more neighboring country adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33–0.75). For each 1% increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00–1.04). Global recommendations and local studies were not associated with time to decision.
Conclusions
This study substantiates previous findings related to vaccine price and presents new evidence to suggest that GAVI eligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboring country decisions was also highly significant, suggesting that approaches to support the adoption of new vaccines should consider supply- and demand-side factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, immunization averts more than 2 million deaths by preparing people's immune systems to recognize and attack disease-causing organisms (pathogens) rapidly and effectively. Although the immune system is designed to protect the human body against infections, the first time a person is exposed to a pathogen (usually during early childhood) their immune system can take some time to respond. As a result, they can become seriously ill or even die. However, the immune system “learns” from the experience and when the pathogen is encountered again, the immune system swings into action much more quickly. Immunization or vaccination is a safe way to make individuals resistant to infectious diseases. It works by exposing them to weakened or dead pathogens or to pathogen molecules (antigens) that the immune system recognizes as foreign. Widespread, routine immunization of children is, therefore, an essential component of national and global strategies to reduce childhood illnesses and deaths.
Why Was This Study Done?
Although many factors affect the uptake of immunization (in particular, vaccine prices), national policy decisions to adopt new vaccines are an essential step toward improving coverage. Unfortunately, these decisions are often delayed in developing countries. Thus, although many industrialized countries have routinely immunized their children with the highly effective Haemophilus influenza type b (Hib) conjugate vaccine since it became available in the early 1990s, only 13 low-income countries were using the vaccine in 2004. Hib bacteria, which cause pneumonia (lung infection) and meningitis (brain inflammation), kill about 370,000 unvaccinated young children every year. In this study, the researchers try to explain delays in the adoption of routine Hib vaccination in developing countries by analyzing the associations between Hib vaccination and factors such as national economic status, local Hib burden, and eligibility for support from the Global Alliance for Vaccines and Immunisation (GAVI Alliance; a public–private partnership that offers financial, technical, and health systems support for the introduction of national immunization programs to developing countries that meet certain eligibility criteria).
What Did the Researchers Do and Find?
The researchers used a statistical approach called accelerated failure time analysis to analyze data collected in 147 countries between 1990 and 2007 on vaccine costs, Hib disease incidence, GAVI eligibility, and other factors that could influence decision-makers' perceptions of the costs and benefits of Hib vaccination. After allowing for gross national income, region, and burden of Hib disease, the researchers identified several factors that influenced the time between the availability of a Hib conjugate vaccine in a country and a decision being made to introduce routine Hib vaccination. The receipt of GAVI support speeded the decision to adopt vaccination by 63%, for example, and sharing borders with two or more countries that had adopted the vaccine speeded the decision by 50%. By contrast, for each 1% increase in vaccine costs, the time to decision to adopt vaccination was delayed by 2%. The 1998 and 2006 World Health Organization recommendations on routine Hib vaccination and the existence of local studies on Hib disease had no influence on the time to decision.
What Do These Findings Mean?
These findings confirm previous studies that showed that increases in the price of Hib vaccine increase the time to adoption. In addition, they suggest that GAVI eligibility accelerates decisions to adopt this vaccine and show that the decisions made by neighboring countries are important, which suggests that policy diffusion may occur. Thus, in the case of adoption of the Hib vaccine, both supply-side and demand-side factors seem to be important. Its is relevant to note that during writing of the article, JCS, MLS, MRR, APB, and RAH were employed by the Hib Initiative, which was funded by the GAVI Alliance. The findings do not necessarily represent the views, policies or decisions of the Hib Initiative or the GAVI Alliance. Importantly, these findings are explanatory, not predictive, so they cannot be applied directly to new vaccines to improve their rate of adoption. Nevertheless, these findings highlight the potential importance of setting up formal and informal networks to facilitate policy diffusion and suggest that long-term price and supply certainty might be factors that could help to accelerate national decisions to adopt new and/or underutilized vaccines and other public-health technologies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000249.
The World Health Organization provides information on immunization and on Haemophilus influenza type b (in several languages)
The GAVI Alliance Web site describes the work of this public–private partnership and provides details of developing countries eligible for Hib vaccination support
The Hib Initiative aims to reduce the risk of childhood death and disability through sustained use of Hib vaccine
MedlinePlus provides links to further resources on immunization and information on the Haemophilus influenzae type b vaccine (in English and Spanish)
doi:10.1371/journal.pmed.1000249
PMCID: PMC2838745  PMID: 20305714
21.  Factors That Influence Vaccination Decision-Making by Parents Who Visit an Anthroposophical Child Welfare Center: A Focus Group Study 
In recent years, parents have become more disparaging towards childhood vaccination. One group that is critical about the National Immunization Program (NIP) and participates less comprises parents with an anthroposophical worldview. Despite the fact that various studies have identified anthroposophists as critical parents with lower vaccination coverage, no research has been done to explore the beliefs underlying their childhood vaccination decision-making. We conducted a qualitative study using three focus groups (n = 16) of parents who visit an anthroposophical child welfare center. Our findings show that participants did not refuse all vaccinations within the Dutch NIP, but mostly refused the Mumps, Measles, and Rubella (MMR) vaccination. Vaccination decisions are influenced by participants' lifestyle, perception of health, beliefs about childhood diseases, perceptions about the risks of diseases, perceptions about vaccine effectiveness and vaccine components, and trust in institutions. Parents indicated that they felt a need for more information. Sufficient references should be provided to sources containing more information about childhood vaccination, especially about the effectiveness of vaccines and vaccine components and the risks, such as possible side effects and benefits of vaccination. This may satisfy parents' information needs and enable them to make a sufficiently informed choice whether or not to vaccinate their child.
doi:10.1155/2012/175694
PMCID: PMC3508517  PMID: 23209917
22.  Factors associated with seasonal influenza vaccine uptake among children in Japan 
Background
Seasonal influenza vaccine was once part of the routine immunization schedule that is routinely offered to all children in Japan, but it is now excluded from the schedule. This study aimed to investigate factors influential to parents’ decision to have their children receive seasonal influenza vaccine, as well as types of seasonal influenza vaccine information that is given to parents.
Methods
We conducted a cross-sectional online survey of 555 participants who have at least one child younger than 13 years of age. Respondents were asked to categorize the history of influenza vaccination of their youngest child as either ‘annual’ , ‘sometimes’ , or ‘never’. Participants were also asked about potentially influential factors in their decision to have their children receive a seasonal influenza vaccine.
Results
A total of 75% of respondents answered that their youngest child had received a seasonal influenza vaccine, and 57% of respondents answered that their child receives the vaccine every year. The higher income group was more likely than the lowest income group to have a history of influenza vaccine uptake. A recommendation from a pediatrician or school/nursery to have their child vaccinated was also positively associated with a history of influenza vaccine uptake. The most common reason for a pediatrician’s recommendation was ‘it leads to milder symptoms if infected’.
Conclusions
The main finding of the study is a significant association between household income and influenza vaccination of the youngest child in the household. We also found that cost could be a barrier to vaccinating children in low income households and that information from pediatricians and schools/nurseries could motivate parents to have their children vaccinated.
doi:10.1186/s12879-015-0821-3
PMCID: PMC4335773
Seasonal influenza vaccine; Self-paid vaccine; Voluntary vaccination; Children
23.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
24.  Use of the internet by parents of paediatric outpatients 
Archives of Disease in Childhood  2002;87(6):534-536.
Aims: (1) To establish how many parents of children seen in paediatric outpatient departments use the internet to find information about their child's medical condition. (2) To ascertain what information is sought and found, and what proportion of all parents had access to the internet at home or elsewhere.
Methods: Over a six week period in 2000, parents of children attending general paediatric outpatient clinics in the district general hospital in Bath and in the 10 associated community hospitals, were asked to complete a questionnaire survery.
Results: Of the 577 questionnaires distributed, 485 were returned, a response rate of 84%. A total of 332 (69%) families owned a computer and 248 (51%) had internet access; 107 (22%) had looked on the internet for information about the problem for which their child was being seen in clinic that day. Parents who knew their child's diagnosis were more likely to have used the internet than those who named their child's symptoms only. A health professional had suggested that parents seek information on the internet in 6% of cases. These parents were more likely to use the internet than parents to whom this had not been suggested (67% v 20%, p < 0.001). Eighty nine (84%) parents who had used the internet prior to this clinic appointment found it useful. Thirty six (34%) parents had discussed or were planning to discuss the information they had found with their doctors.
Conclusion: A significant proportion of parents have access to the internet and use it to find information about their child's medical condition. The parents who discuss what they find with the clinic doctor are in the minority. Doctors should be prepared to ask parents about their information needs and discuss use of the internet.
doi:10.1136/adc.87.6.534
PMCID: PMC1755829  PMID: 12456558
25.  The Impact of Search Engine Selection and Sorting Criteria on Vaccination Beliefs and Attitudes: Two Experiments Manipulating Google Output 
Background
During the past 2 decades, the Internet has evolved to become a necessity in our daily lives. The selection and sorting algorithms of search engines exert tremendous influence over the global spread of information and other communication processes.
Objective
This study is concerned with demonstrating the influence of selection and sorting/ranking criteria operating in search engines on users’ knowledge, beliefs, and attitudes of websites about vaccination. In particular, it is to compare the effects of search engines that deliver websites emphasizing on the pro side of vaccination with those focusing on the con side and with normal Google as a control group.
Method
We conducted 2 online experiments using manipulated search engines. A pilot study was to verify the existence of dangerous health literacy in connection with searching and using health information on the Internet by exploring the effect of 2 manipulated search engines that yielded either pro or con vaccination sites only, with a group receiving normal Google as control. A pre-post test design was used; participants were American marketing students enrolled in a study-abroad program in Lugano, Switzerland. The second experiment manipulated the search engine by applying different ratios of con versus pro vaccination webpages displayed in the search results. Participants were recruited from Amazon’s Mechanical Turk platform where it was published as a human intelligence task (HIT).
Results
Both experiments showed knowledge highest in the group offered only pro vaccination sites (Z=–2.088, P=.03; Kruskal-Wallis H test [H5]=11.30, P=.04). They acknowledged the importance/benefits (Z=–2.326, P=.02; H5=11.34, P=.04) and effectiveness (Z=–2.230, P=.03) of vaccination more, whereas groups offered antivaccination sites only showed increased concern about effects (Z=–2.582, P=.01; H5=16.88, P=.005) and harmful health outcomes (Z=–2.200, P=.02) of vaccination. Normal Google users perceived information quality to be positive despite a small effect on knowledge and a negative effect on their beliefs and attitudes toward vaccination and willingness to recommend the information (χ2 5=14.1, P=.01). More exposure to antivaccination websites lowered participants’ knowledge (J=4783.5, z=−2.142, P=.03) increased their fear of side effects (J=6496, z=2.724, P=.006), and lowered their acknowledgment of benefits (J=4805, z=–2.067, P=.03).
Conclusion
The selection and sorting/ranking criteria of search engines play a vital role in online health information seeking. Search engines delivering websites containing credible and evidence-based medical information impact positively Internet users seeking health information. Whereas sites retrieved by biased search engines create some opinion change in users. These effects are apparently independent of users’ site credibility and evaluation judgments. Users are affected beneficially or detrimentally but are unaware, suggesting they are not consciously perceptive of indicators that steer them toward the credible sources or away from the dangerous ones. In this sense, the online health information seeker is flying blind.
doi:10.2196/jmir.2642
PMCID: PMC4004139  PMID: 24694866
consumer health information; search engine; searching behavior; Internet; information storage and retrieval; online systems; public health informatics; vaccination; health communication

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