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1.  Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in Olive baboons 
Vaccine  2013;31(31):3140-3147.
Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (Olive baboons, Papio anubis). The results showed that at a dose of 2.5 mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5 mg and 1 mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers.
PMCID: PMC3686897  PMID: 23684840
Pfs25; Malaria; Transmission blocking vaccine; DNA vaccine; Electroporation; Prime boost
2.  Correlates of HPV Vaccination among Adolescent Females from Appalachia and Reasons Why Their Parents Do Not Intend to Vaccinate 
Vaccine  2013;31(31):3121-3125.
Limited research has examined HPV vaccination in Appalachia, a region with cervical cancer disparities. We analyzed 2008–2010 National Immunization Survey-Teen data for adolescent females ages 13–17 from Appalachia (n=1,951) to identify correlates of HPV vaccination and reasons why their parents do not intend to vaccinate. HPV vaccine initiation was 40.8%, completion was 27.7%, and follow-through was 67.8%. Vaccination outcomes tended to be higher among females who were older, had visited their healthcare provider in the last year, or whose parents reported receiving a provider recommendation to vaccinate. Only 41.0% of parents with unvaccinated daughters intended to vaccinate in the next year. The most common reasons for not intending to vaccinate were believing vaccination is not needed or not necessary (21.5%) and lack of knowledge (18.5%). Efforts to reduce missed opportunities for vaccination at healthcare visits and address reasons why parents are not vaccinating may help increase HPV vaccination in Appalachia.
PMCID: PMC3705728  PMID: 23664990
Human papillomavirus; HPV vaccine; Appalachia; Cancer; NIS-Teen
3.  Randomized, Double-Blind, Placebo-Controlled, Safety and Immunogenicity Study of 4 Formulations of Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909) in Healthy Adult Volunteers 
Vaccine  2013;31(30):3051-3058.
A new anthrax vaccine that could accelerate the immune response and possibly reduce the number of injections needed for protection would be desirable in a post-exposure setting.
This Phase 1 study compared the safety and immunogenicity of 2 IM doses (Days 0 and 14) of 4 formulations of AV7909 (AVA plus CPG 7909) with 2 IM doses of BioThrax® (Anthrax Vaccine Adsorbed) and 2 IM doses of saline placebo administered on Days 0 and 14.
A total of 105 healthy adults 18 to 50 years of age were randomized to 1 of 6 study groups: BioThrax (0.5 mL), AV7909 Formulation 1 (0.5 mL AVA + 0.5 mg CPG 7909), AV7909 Formulation 2 (0.5 mL AVA + 0.25 mg CPG 7909), AV7909 Formulation 3 (0.25 mL AVA + 0.5 mg CPG 7909), AV7909 Formulation 4 (0.25 mL AVA + 0.25 mg CPG 7909), or saline placebo (0.5 mL). All randomized subjects received at least 1 vaccination, and 100 subjects completed the trial.
After 2 doses, mean peak normalized toxin neutralizing antibody responses (TNA NF50) in the AV7909 groups were higher than in the BioThrax group. Differences among the 4 AV7909 groups were not statistically significant. Subjects who received AV7909 reached peak titers on Day 28 vs. Day 35 in the BioThrax group.
The most common adverse events (AEs) in the BioThrax and AV7909 groups assessed as related to vaccination were injection site reactions. Transient lymphopenia was observed after the first dose in each AV7909 group. Frequencies of injection site and systemic reactions recorded by subjects in diaries for 7 days after each injection were highest with AV7909 Formulation 1. No AEs of special interest (autoimmune events) were observed in the study.
Further studies of doses and dosing regimens are planned to assess the immunogenicity and reactogenicity of AV7909.
PMCID: PMC3687017  PMID: 23701746
BioThrax® (Anthrax Vaccine Adsorbed); Anthrax; Vaccine; CPG 7909; AV7909; Post-exposure prophylaxis
4.  A novel tetrameric gp3501-470 as a potential Epstein-Barr virus vaccine 
Vaccine  2013;31(30):3039-3045.
Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp3501-470). Tetrameric gp3501-470 induced ~20-fold higher serum titers of gp3501-470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp3501-470. Further, epidermal immunization with plasmid DNA encoding gp3501-470 tetramer induced 8-fold higher serum titers of gp3501-470-specific IgG relative to monomer. Tetrameric gp3501-470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp3501-470 had no effect on the gp3501-470-specific IgG response in naïve mice, and resulted in suppressed gp3501-470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp3501-470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest.
PMCID: PMC3700395  PMID: 23665339
EBV; vaccine; antibody; multimer; CD21; mononucleosis
5.  Optimal targeting of seasonal influenza vaccination toward younger ages is robust to parameter uncertainty 
Vaccine  2013;31(30):3079-3089.
Identification of the optimal vaccine allocation for the control of influenza requires consideration of uncertainty arising from numerous unpredictable factors, including viral evolution and diversity within the human population’s immunity as well as variation in vaccine efficacy. The best policy must account for diverse potential outcomes based on these uncertainties. Here we used a mathematical model parametrized with survey-based contact data, demographic, and epidemiological data from seasonal influenza in the United States to determine the optimal vaccine allocation for five outcome measures: infections, hospitalizations, deaths, years of life loss, and contingent valuation. We incorporated uncertainty of epidemiological parameters and derive probability distributions of optimal age- and risk-specific allocation of vaccine. Our analysis demonstrated that previous recommendations of targeting schoolchildren (ages 5–17 years) and young adults (18–44 years) are generally robust in the face of uncertainty. However, when the outcome measure is to minimize deaths, years of life loss, or contingent valuation, uncertainty analysis identified scenarios under which it is optimal to target people at high risk for complications, even when vaccine are in abundance.
PMCID: PMC3764605  PMID: 23684837
Seasonal influenza; Vaccination; Mathematical modeling; Optimization
6.  CD4+ T-cell Responses Among Adults and Young Children In Response to Streptococcus pneumoniae and Haemophilus influenzae Vaccine Candidate Protein Antigens 
Vaccine  2013;31(30):3090-3097.
We characterized cytokine profiles of CD4+ T-helper (h) cells in adults and young children to ascertain if responses occur to next-generation candidate vaccine antigens PspA, PcpA, PhtD, PhtE, Ply, LytB of Streptococcus pneumonia (Spn) and Protein D and OMP26 of non-typeable Haemophilus influenzae (NTHi). Adults had vaccine antigen-specific Th1 - and Th2 cells responsive to all antigens evaluated whereas young children had significant numbers of vaccine antigen-specific CD4+ T cells producing IL-2, (p=0.004). Vaccine antigen-specific CD4+ T-cell populations in adults were largely of effector (TEM) and/or central memory (TCM) phenotypes as defined by CD45RA−CCR7+ or CD45RA−CCR7− respectively; however among young children antigen-specific IL-2 producing CD4+ T cells demonstrated CD45RA+ expression (non-memory cells). We conclude that adults have circulating memory CD4+T cells (CD45RA−) that can be stimulated by all the tested Spn and NTHi protein vaccine candidate antigens, whereas young children have a more limited response.
PMCID: PMC3777711  PMID: 23632305
Streptococcus pneumonia; non-typeable Haemophilus influenzae; CD4+ T-helper (h) cell; IFN-y; IL-2; memory T cells
7.  Safety and Immunogenicity of IMVAMUNE® Smallpox Vaccine Using Different Strategies for a Post Event Scenario 
Vaccine  2013;31(29):3025-3033.
Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic’s (BN) IMVAMUNE® (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0 and 28 day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses.
Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination.
The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group:0+7, Group:0+28 and Group:0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group:0+7, Group:0+28, and Group:0, respectively (Chi-square test P value=0.77). Based on BN’s Plaque Reduction Assay GMTs, Group:0+7 was non-inferior to Group:0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group:0+7 and Group:0+28 GMT were 10.8 (CI:9.0;12.9) and 30.2 (CI:22.1;41.1), respectively. Based on BN’s Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group:0+28 was significantly greater than that for Group:0+7 after second vaccination at Day 4 and 180. By Day 14 after the second dose, the IFN-y Enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group:0+28 and Group:0+7.
Overall, a standard dose of IMVAMUNE (0.5mL of 1×108 TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-y ELISPOT responses were similar for Group:0+28 and Group:0+7.
PMCID: PMC3755481  PMID: 23664987
MVA; IMVAMUNE; smallpox; vaccine; bioterrorism; post-event
8.  Modeling the impact of quadrivalent HPV vaccination on the incidence of Pap test abnormalities in the United States 
Vaccine  2013;31(29):3019-3024.
We present data on Pap test results and HPV prevalence from the HPV Sentinel Surveillance project, a multiyear surveillance project enrolling women from a diverse set of 26 clinics throughout the US from 2003 to 2005. We use mathematical modeling to illustrate the potential timing and magnitude of decreases in Pap test abnormalities in sexually transmitted disease (STD), family planning, and primary care clinics in the US as a result of HPV vaccination.
The probability of an abnormal Pap result was based on three factors: (1) infection with HPV 16/18, or both; (2) infection with high-risk HPV types other than HPV 16/18; and (3) infection with HPV 6/11, or both. We estimated the relative reduction in the probability of an abnormal Pap result over the first 25 years of a female-only, quadrivalent HPV vaccination program, compared to a scenario of no HPV vaccination in which the probability of abnormal Pap results was assumed constant.
The probability of an abnormal Pap result ranged from 7.0% for the lowest risk group (those without any high-risk HPV types and without HPV 6/11) to 45.2% for the highest risk group (those with HPV 16/18 and at least one other high-risk HPV type). Estimated reductions in abnormal Pap results among women in the 21- to 29-year age group were 0.8%, 10.2%, and 11.3% in years 5, 15, and 25 of the vaccine program respectively, in the lower vaccine coverage scenario, and 7.4%, 21.4%, and 22.2%, respectively, in the higher coverage scenario.
Our results suggest that HPV vaccination will have a discernable impact on the probability of Pap abnormalities, but the timing and magnitude of the reduction will depend substantially on vaccine coverage and the degree of cross-protection against high risk HPV types other than HPV 16/18.
PMCID: PMC3998647  PMID: 23664991
HPV; HPV vaccine; Papanicolaou test; Vaccination effects
9.  Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle 
Vaccine  2013;31(28):2954-2962.
Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10 to 40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel® had a 75 to 110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel® formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel® formulation is ongoing in the United States.
PMCID: PMC3683851  PMID: 23623858
Pfs25; malaria; transmission blocking vaccine; nanoparticle; chemical-conjugate; recombinant protein
10.  Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD 
Vaccine  2013;31(28):2919-2929.
Shigella spp. are food- and water-borne pathogens that cause shigellosis, a severe diarrheal and dysenteric disease that is associated with a high morbidity and mortality in resource-poor countries. No licensed vaccine is available to prevent shigellosis. We have recently demonstrated that Shigella invasion plasmid antigens (Ipas), IpaB and IpaD, which are components of the bacterial type III secretion system (TTSS), can prevent infection in a mouse model of intranasal immunization and lethal pulmonary challenge. Because they are conserved across Shigella spp. and highly immunogenic, these proteins are excellent candidates for a cross-protective vaccine. Ideally, such a vaccine could be administered to humans orally to induce mucosal and systemic immunity. In this study, we investigated the immunogenicity and protective efficacy of Shigella IpaB and IpaD administered orally with a double mutant of the Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant. We characterized the immune responses induced by oral vs. intranasal immunization and the protective efficacy using a mouse pulmonary infection model. Serum IgG and fecal IgA against IpaB were induced after oral immunization. These responses, however, were lower than those obtained after intranasal immunization despite a 100-fold dosage increase. The level of protection induced by oral immunization with IpaB and IpaD was 40%, while intranasal immunization resulted in 90% protective efficacy. IpaB- and IpaD-specific IgA antibody-secreting cells in the lungs and spleen and T-cell-derived IL-2, IL-5, IL-17 and IL-10 were associated with protection. These results demonstrate the immunogenicity of orally administered IpaB and IpaD and support further studies in humans.
PMCID: PMC3718310  PMID: 23644075
Shigella vaccines; oral immunization; type III secretion proteins
11.  Vaccination of horses with a recombinant modified vaccinia Ankara virus (MVA) expressing African horse sickness (AHS) virus major capsid protein VP2 provides complete clinical protection against challenge 
Vaccine  2014;32(29):3670-3674.
•A recombinant modified Vaccinia Ankara virus expressing VP2 of African horse sickness virus serotype 9 was generated.•Four horses were vaccinated on days 0 and 20. Three unvaccinated controls were used.•Vaccinated and control horses were challenged intravenously with 107.4TCID50 of AHSV-9 on day 34 of the study.•At challenge, vaccinates had virus neutralising antibodies but were negative for antibodies to AHSV-VP7.•All vaccinates were completely protected against clinical signs of African horse sickness.
African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant modified vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against virulent AHSV challenge.
This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection.
These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field.
PMCID: PMC4061461  PMID: 24837765
African horse sickness; Vaccine; Modified vaccinia Ankara; VP2; Protection
Vaccine  2013;31(27):10.1016/j.vaccine.2013.04.032.
Meat contamination by Salmonella spp is emerging as a major cause of human enteric infections in industrialized countries. The attempts to reduce human cases of salmonellosis encompass pre- and post harvest interventions. In this context, vaccination of pigs may represent an effective instrument in eliminating/reducing Salmonella burden through the food chain. We have previously demonstrated that Salmonella Typhimurium lacking the ZnuABC transporter (S. Typhimurium ΔznuABC) is a promising candidate live vaccine in different mouse models of Salmonella Typhimurium infection. In this study, we confirmed in pigs the attenuation of S. Typhimurium ΔznuABC. Moreover, we evaluated the safety and immunogenicity of S. Typhimurium ΔznuABC administered to pigs by the oral route. We monitored clinical conditions of animals and we conducted a microbiological culture and a quantification of the humoral and cellular immune response, respectively, on faecal and blood samples of pigs. After vaccination with attenuated S. Typhimurium ΔznuABC, pigs showed a modest degree of hyperthermia. In addition, faecal shedding of S. Typhimurium ΔznuABC could not be detected 28 days after the inoculum. Furthermore, vaccination with S. Typhimurium ΔznuABC elicited a distinct production of anti-Salmonella antibodies and IFN-γ. Taken together, these results suggest that S. Typhimurium ΔznuABC is attenuated and immunogenic in pigs. Although the vaccine dosages do not guarantee complete safety there is ample margin to set up better conditions of use, suggesting that S. Typhimurium ΔznuABC could be a promising attenuated strain to be used as live mucosal vaccine for oral delivery.
PMCID: PMC3874890  PMID: 23623860
Vaccine; Salmonella; Pig; Safety; Immunogenicity
13.  HPV Vaccination among Adolescent Males: Results from the National Immunization Survey-Teen 
Vaccine  2013;31(26):2816-2821.
US guidelines provided a permissive recommendation forHPV vaccine for males in 2009, with an updated recommendation for routine vaccination in 2011. Dataon vaccine uptake among males, however, remain sparse. We analyzed 2010–2011 data (collected mostlyprior to the recommendation for routine vaccination) from the National Immunization Survey-Teen for a nationally representative sample of adolescent males ages 13–17 (n=22,365). We examined HPV vaccine initiation( receipt of at least one doseba sed on healthcare provider records) as the primary outcome. Analyses used weighted logistic regression. HPV vaccine initiation increased from 1.4% in 2010 to 8.3% in 2011. Parents who reported receiving a healthcare provider recommendation to get their sons HPV vaccine were much more likely to have vaccinated sons (OR=19.02, 95% CI: 14.36–25.19). Initiation was also higher among sons who were Hispanic (OR=1.83, 95% CI: 1.24–2.71) or who were eligible for the Vaccines for Children program (OR=1.53, 95% CI: 1.01–2.31). Only31.0% of parents with unvaccinated sons indicatedtheir sons were “somewhat likely” or “very likely” to receive HPV vaccine in the next year. The most common main reasons for parents not intending to vaccinate were believing vaccination is not needed or not necessary (24.5%), not having received a provider recommendation (22.1%), and lack of knowledge (15.9%). HPV vaccination is low among adolescent males in the US, and provider recommendation for vaccination is likely keyto improv ingvaccine uptake. Given the updated recommendation for routine vaccination and the changes in health insurance coverage that are likely to follow, continued efforts are needed to monitor HPV vaccination among males.
PMCID: PMC3672374  PMID: 23602667
HPV; HPV vaccine; Males; NIS-Teen; Adolescent Health
14.  Removing the Regional Level from the Niger Vaccine Supply Chain 
Vaccine  2013;31(26):2828-2834.
Since many of the world’s vaccine supply chains contain multiple levels, the question remains of whether removing a level could bring efficiencies.
We utilized HERMES to generate a detailed discrete-event simulation model of Niger’s vaccine supply chain and compare the current four-tier (central, regional, district and integrated health center levels) with a modified three-tier structure (removing the regional level). Different scenarios explored various accompanying shipping policies and frequencies.
Removing the regional level and implementing a collection-based shipping policy from the district stores increases vaccine availability from a mean of 70% to 100% when districts could collect vaccines at least weekly. Alternatively, implementing a delivery-based shipping policy from the central store monthly in three-route and eight-route scenarios only increases vaccine availability to 87%. Restricting central-to district vaccine shipments to a quarterly schedule for three-route and eight-route scenarios reduces vaccine availability to 49%. The collection-based shipping policy from district stores reduces supply chain logistics cost per dose administered from US$0.14 at baseline to US$0.13 after removing the regional level.
Removing the regional level from Niger’s vaccine supply chain can substantially improve vaccine availability as long as certain concomitant adjustments to shipping policies and frequencies are implemented.
PMCID: PMC3763189  PMID: 23602666
Vaccine Supply Chain; Niger; Immunization; Vaccine Delivery; Vaccine Distribution
15.  Immune Response to Vaccine Adjuvants during the First Year of Life 
Vaccine  2012;31(21):2500-2505.
Subunit vaccine formulations often include adjuvants that primarily stimulate innate immune cells. While young infants represent the major target population for vaccination, effective immunization in this age group remains a challenge. Many parameters of innate immune responses differ quantitatively and qualitatively from newborns to infants and adults, revealing a highly regulated developmental program. Herein, we discuss the potential implications of innate immune ontogeny for the activity of adjuvants contained in licensed infant vaccines, as well as future directions for rational design of adjuvanted vaccines for this age group.
PMCID: PMC4048858  PMID: 23085363
adjuvants; innate immunity; vaccines; newborn; infant; immunization
16.  Evaluation of Vaccine-induced Antibody Responses: Impact of New Technologies 
Vaccine  2013;31(25):2756-2761.
Host response to vaccination has historically been evaluated based on a change in antibody titer that compares the post-vaccination titer to the pre-vaccination titer. A four-fold or greater increase in antigen-specific antibody has been interpreted to indicate an increase in antibody production in response to vaccination. New technologies, such as the bead-based assays, provide investigators and clinicians with precise antibody levels (reported as concentration per mL) in ranges below and above those previously available through standard assays such as ELISA. Evaluations of bead assay data to determine host response to vaccination using fold change and absolute change, witha general linear models used to calculate adjusted statistics, present very different pictures of the antibody response when pre-vaccination antibody levels are low. Absolute changes in bead assay values, although not a standard computation, appears to more accurately reflect the host response to vaccination for those individuals with extremely low pre-vaccination antibody levels. Conversely, for these same individuals, fold change may be very high while post-vaccination antibodies do not achieve seroprotective levels. Absolute change provides an alternate method to characterize host response to vaccination, especially when pre-vaccination levels are very low, and may be useful in studies designed to determine associations between host genotypes and response to vaccination.
PMCID: PMC3672347  PMID: 23583812
seroconversion; change score; typhoid; vaccine; statistics
17.  α1-giardin based live heterologous vaccine protects against Giardia lamblia infection in a murine model 
Vaccine  2011;29(51):9529-9537.
Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide, yet preventive medical strategies are not available. A crude veterinary vaccine has been licensed for cats and dogs, but no defined human vaccine is available. We tested the vaccine potential of three conserved antigens previously identified in human and murine giardiasis, α1-giardin, α-enolase, and ornithine carbamoyl transferase, in a murine model of G. lamblia infection. Live recombinant attenuated Salmonella enterica Serovar Typhimurium vaccine strains were constructed that stably expressed each antigen, maintained colonization capacity, and sustained total attenuation in the host. Oral administration of the vaccine strains induced antigen-specific serum IgG, particularly IgG2A, and mucosal IgA for α1-giardin and α-enolase, but not for ornithine carbamoyl transferase. Immunization with the α1-giardin vaccine induced significant protection against subsequent G. lamblia challenge, which was further enhanced by boosting with cholera toxin or sublingual α1-giardin administration. The α-enolase vaccine afforded no protection. Analysis of α1-giardin from divergent assemblage A and B isolates of G. lamblia revealed >97% amino acid sequence conservation and immunological cross-reactivity, further supporting the potential utility of this antigen in vaccine development. Together. these results indicate that α1-giardin is a suitable candidate antigen for a vaccine against giardiasis.
PMCID: PMC4045459  PMID: 22001876
Giardiasis; live oral vaccines; animal models
18.  Breast milk and Group B streptococcal infection: Vector of transmission or vehicle for protection? 
Vaccine  2014;32(26):3128-3132.
•GBS has been implicated in late onset-disease cases associated with breast milk.•Proposed mechanisms include transfer of bacteria from the colonization of the infant to the milk ducts during suckling.•Serotype-specific IgA antibody to GBS in breast milk may provide additional protection from invasive GBS disease.•Vaccination of mothers in pregnancy may enable higher GBS-antibody concentrations to pass in breast milk.
Invasive Group-B streptococcal (GBS) disease is a leading cause of infant mortality and morbidity worldwide. GBS colonises the maternal rectum and vagina and transmission of bacteria from a colonized mother to her infant at birth is an important risk factor for GBS disease. GBS disease has also been associated with case reports of transmission via infected breast milk raising questions about mode of acquisition and transmission of this enteric pathogen and the development of neonatal disease. However, most breastfed infants remain unaffected by GBS in breast milk. Mechanisms associated with transmission of GBS in breast milk and potential factors that may protect the infant from transmission remain poorly understood. Understanding factors involved in protection or transmission of GBS infection via breast milk is important both for premature infants who are a high-risk group and for infants in the developing world where breastfeeding is the only sustainable infant feeding option. In this review we discuss the proposed mechanisms for GBS colonization in breast milk on one hand and its immune factors that may protect from transmission of GBS from mother to infant on the other. Innate and adaptive immune factors, including serotype-specific antibody and their significance in the prevention of infant disease are presented. We further report on the role of human oligosaccharides in protection from invasive GBS disease. Advances in our knowledge about breast milk and immunity in GBS disease are needed to fully appreciate what might mitigate transmission from mother to infant and protect neonates from this devastating disease and to contribute to the development of novel prevention strategies, including maternal immunization to prevent infant disease.
PMCID: PMC4037808  PMID: 24736004
Group-B streptococcus; Breast milk; Immunity; Antibody; Vaccination
19.  Measles, mumps and rubella (MMR) vaccination has no effect on cognitive development in children – the results of the Polish prospective cohort study 
Vaccine  2013;31(22):2551-2557.
The aim of the study was to examine the hypothesis that MMR exposure has a negative influence on cognitive development in children. Furthermore, MMR was compared to single measles vaccine to determine the potential difference of these vaccines safety regarding children’s cognitive development.
The prospective birth cohort study with sample consisted of 369 infants born in Krakow. Vaccination history against measles (date and the type of the vaccine) was extracted from physicians’ records. Child development was assessed using the Bayley Scales of Infant Development (BSID-II) up to 3rd year of life, Raven test in 5th and 8th year and Wechsler (WISC-R) in 6th and 7th year. Data on possible confounders came from mothers’ interview, medical records and analyses of lead and mercury level at birth and at the end of 5th year of life. Linear and logistic regression models adjusted for potential confounders were used to assess the association.
No significant differences in cognitive and intelligence tests results were observed between children vaccinated with MMR and those not vaccinated up to the end of the 2nd year of life. Children vaccinated with MMR had significantly higher Mental BSID-II Index (MDI) in the 36th month than those vaccinated with single measles vaccine (103.8±10.3 vs. 97.2±11.2, p=0.004). Neither results of Raven test nor WISC-R were significantly different between groups of children vaccinated with MMR and with single measles vaccine. After standardization to child’s gender, maternal education, family economical status, maternal IQ, birth order and passive smoking all developmental tests were statistically insignificant.
The results suggest that there is no relationship between MMR exposure and children’s cognitive development. Furthermore, the safety of triple MMR is the same as the single measles vaccine with respect to cognitive development.
PMCID: PMC3684783  PMID: 23588083
children; MMR vaccine; cognitive development
20.  Complement and Humoral Immunity 
Vaccine  2008;26(0 8):I28-I33.
The complement system was discovered almost a century ago as an important effector in antibody-dependent killing of microorganisms. Since this early period much was learned about the biochemistry and structure of complement proteins and their function in mediating inflammation. More recently, a prominent role for complement was identified in linkage of innate and adaptive immunity. In this review, I will discuss our current understanding of the importance of complement in enhancing the humoral immune response to both model antigens and pathogens. As discussed below, it is evident that the complement system participates in marking of “foreign” pathogens and “presenting” them to B cells in a manner that enhances both antibody production and long term memory. In this special issue of Vaccine, we see examples of how complement is critical in the immune response to bacterial and viral pathogens. Moreover, the finding that most organisms have co-evolved proteins to evade complement detection underscores its importance in host protection.
PMCID: PMC4018718  PMID: 19388161
humoral immunity; innate immunity; complement receptors
21.  Increased efficacy of a trivalent nicotine vaccine compared to a dose-matched monovalent vaccine when formulated with alum 
Vaccine  2013;31(52):6185-6193.
Vaccination against nicotine is a potential treatment for tobacco smoking. Clinical trials show effect only in high antibody responders; therefore it is necessary to increase the effectiveness of nicotine vaccines. The use of a multivalent vaccine that activates several B cell populations is a possible approach to increase antibody response. The aim of this study was to investigate whether three different nicotine immunogens could be mixed to generate independent responses resulting in additive antibody titers, and whether this would alter nicotine distribution to a greater extent than antibodies generated by a monovalent vaccine. When immunogens were administered s.c. with alum adjuvant, the trivalent vaccine generated significantly higher titers and prevented the distribution of an i.v. nicotine dose to brain to a greater extent than an equivalent dose of a monovalent vaccine. The number of rats with antibody titers >1:10,000 was significantly increased in the trivalent group compared to the monovalent group. There were no correlations between the titers generated by the different nicotine immunogens in the trivalent vaccine, supporting the hypothesis that the immunogens generated independent responses from distinct populations of B cells. In contrast, when administered i.p. in Freund’s adjuvant, the trivalent nicotine vaccine was not more immunogenic than its component monovalent vaccine. Vaccine immunogenicity was suppressed if unconjugated protein was added to the monovalent vaccine formulated in Freund’s adjuvant, compared to monovalent vaccine alone. These data suggest a protein–protein interaction that affects titers negatively and is apparent when the vaccines are formulated with Freund’s adjuvant. In summary, a trivalent nicotine vaccine formulated with alum showed significantly higher efficacy than a dose-matched monovalent vaccine and may offer a strategy for increasing nicotine vaccine immunogenicity. This approach may be generalizable to other nicotine immunogens or vaccines for other addictive drugs.
PMCID: PMC4019346  PMID: 24176492
Nicotine; Vaccine; Multivalent; Antibody; Tobacco; Immunogen
22.  Clostridium perfringens epsilon toxin mutant Y30A-Y196A as a recombinant vaccine candidate against enterotoxemia 
Vaccine  2014;32(23):2682-2687.
•Etx mutant Y30A-Y196A showed markedly reduced cytotoxicity towards MDCK.2 cells.•Y30A-Y196A is inactive in mice after intraperitoneal administration.•Y30A-Y196A is able to induce a specific antibody response in rabbits.•Y30A-Y196A polyclonal antibody is able to induce protective immunity in vitro.•Y30A-Y196A could form the basis of a recombinant vaccine against enterotoxemia.
Epsilon toxin (Etx) is a β-pore-forming toxin produced by Clostridium perfringens toxinotypes B and D and plays a key role in the pathogenesis of enterotoxemia, a severe, often fatal disease of ruminants that causes significant economic losses to the farming industry worldwide. This study aimed to determine the potential of a site-directed mutant of Etx (Y30A-Y196A) to be exploited as a recombinant vaccine against enterotoxemia. Replacement of Y30 and Y196 with alanine generated a stable variant of Etx with significantly reduced cell binding and cytotoxic activities in MDCK.2 cells relative to wild type toxin (>430-fold increase in CT50) and Y30A-Y196A was inactive in mice after intraperitoneal administration of trypsin activated toxin at 1000× the expected LD50 dose of trypsin activated wild type toxin. Moreover, polyclonal antibody raised in rabbits against Y30A-Y196A provided protection against wild type toxin in an in vitro neutralisation assay. These data suggest that Y30A-Y196A mutant could form the basis of an improved recombinant vaccine against enterotoxemia.
PMCID: PMC4022833  PMID: 24709588
Clostridium perfringens; Epsilon toxin pore-forming toxin; Enterotoxemia; Recombinant vaccine
23.  Mothers’ support for voluntary provision of HPV vaccine in schools 
Vaccine  2011;29(14):2542-2547.
HPV vaccination rates among adolescents in the United States lag behind some other developed countries, many of which routinely offer the vaccine in schools. We sought to assess mothers’ willingness to have their adolescent daughters receive HPV vaccine at school. A national sample of mothers of adolescent females ages 11–14 completed our internet survey (response rate = 66%). The final sample (n = 496) excluded mothers who did not intend to have their daughters receive HPV vaccine in the next year. Overall, 67% of mothers who intended to vaccinate their daughters or had vaccinated their daughters reported being willing to have their daughters receive HPV vaccine at school. Mothers were more willing to allow their daughters to receive HPV vaccine in schools if they had not yet initiated the vaccine series for their daughters or resided in the Midwest or West (all p < .05). The two concerns about voluntary school-based provision of HPV vaccine that mothers most frequently cited were that their daughters’ doctors should keep track of her shots (64%) and that they wished to be present when their daughters were vaccinated (40%). Our study suggests that most mothers who support adolescent vaccination for HPV find school-based HPV vaccination an acceptable option. Ensuring communication of immunization records with doctors and allowing parents to be present during immunization may increase parental support.
PMCID: PMC4018209  PMID: 21300097
HPV vaccine; Vaccination program; Parents; School health; School-based health center
24.  How much will it hurt? HPV vaccine side effects and influence on completion of the three-dose regimen 
Vaccine  2009;27(49):6840-6844.
We examined the prevalence of reported pain following human papillomavirus (HPV) vaccination and whether it differed from that for other adolescent vaccines or affected completion of the HPV vaccine regimen. In 2008, we conducted cross-sectional surveys with parents of adolescent girls aged 11–20 living in areas of North Carolina with elevated cervical cancer rates who had received at least one dose of HPV vaccine. Pain from HPV vaccination, while commonly reported by parents, was less frequent compared to other adolescent vaccines and did not appear to affect vaccine regimen completion. These findings may be important to increase HPV vaccination coverage.
PMCID: PMC4016947  PMID: 19765398
HPV; Vaccine; Side effects
25.  Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model 
Vaccine  2013;31(20):2449-2456.
Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines. We observed that the GPI-anchored cytokines expressed on the surface of tumor cells greatly reduced the overall tumorigenicity of the 4TO7 tumor cells following direct live cell challenge as evidenced by transient tumor growth and complete regression within 30 days post challenge. Tumors co-expressing B7-1 and GPI-IL-12 grew the least and for the shortest duration, suggesting that this combination of immunostimulatory molecules is most potent. Protective immune responses were also observed following secondary tumor challenge. Further, the 4TO7-B7-1/GPI-IL-2 and 4TO7-B7-1/GPI-IL-12 transfectants were capable of inducing regression of a wild-type tumor growing at a distant site in a concomitant tumor challenge model, suggesting the tumor immunity elicited by the transfectants can act systemically and inhibit the tumor growth at a distant site. Additionally, when used as irradiated whole cell vaccines, 4TO7-B7-1/GPI-IL-12 led to a significant inhibition in tumor growth of day 7 established tumors. Lastly, we observed a significant decrease in the prevalence of myeloid-derived suppressor cells and regulatory T-cells in the tumor microenvironment on day 7 post challenge with 4TO7-B7-1/GPI-IL-12 cells, which provides mechanistic insight into antitumor efficacy of the tumor-cell membrane expressed IL-12. These studies have implications in designing membrane-based therapeutic vaccines with GPI-anchored cytokines for breast cancer.
PMCID: PMC3686649  PMID: 23541884
breast cancer; membrane anchored cytokines; antitumor immunity; tumor microenvironment

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