Early rotavirus vaccine adopter countries in the Americas, Europe, and in Australia have documented substantial declines in rotavirus disease burden following the introduction of vaccination. However, the full public health impact of rotavirus vaccines has not been realized as they have not been introduced into routine immunization programs in countries of Africa and Asia with the highest rotavirus disease morbidity and mortality burden. In this article, we review the epidemiology of rotavirus disease, the development and current status of rotavirus vaccines including newly available vaccine impact data from early-introducer countries, and future priorities for implementation and monitoring of rotavirus vaccination programs in developing countries.
rotavirus; gastroenteritis; vaccines; rotavirus vaccines; vaccine impact
It is believed that an effective HCV vaccine must induce strong HCV-specific cytotoxic IFNγ+ CD8+ T cells able to migrate into and become fully activated within the liver, an organ known to suppress T-cell responses and induce tolerance. Given the importance of intrahepatic HCV-specific T cells in the clearance of acute infection, the goal of this present study was to determine if peripheral immunization was able to induce functional intrahepatic HCV-specific T cell-based immunity both in the presence and absence of HCV antigen expression within the liver. Using a novel HCV NS3/NS4A DNA vaccine, we show that peripheral immunization of C57BL/6 mice results in the formation of a large pool of fully functional HCV-specific cytotoxic IFNγ+ CD8+ T cells within the liver and that these cells were highly enriched within the liver as compared with the spleen. Following hepatic expression of cognate HCV antigen using a previously described liver transfection method, we show that this pool of vaccine-induced HCV-specific CD8+ T cells retained its ability to become highly activated as shown by the upregulation of IFNγ and CCR5 expression, as well as by the clearance of HCV NS3 expressing hepatocytes. Taken together, these findings suggest that T-cell effector function is preserved within the liver and that selective recruitment of antigen-specific T cells to the liver may play a previously unappreciated role in the process of immune surveillance, which may be exploited for future T cell-based HCV vaccines.
HCV DNA vaccine; NS3; NS4A; liver transfection; consensus
In the United States, therapeutic vaccines may provide considerable benefit to cancer patients. Yet, there has been no assessment of whether vaccines currently in the research and development pipeline reflect the burden of disease and current survival patterns for different malignancies. The authors used data from the National Cancer Institute, Surveillance Epidemiology and End Results (SEER) database, and clinicaltrials.gov registry to characterize the vaccine development pipeline with respect to 5 measures of disease burden and treatment effectiveness for cancer: annual incidence, annual mortality, five-year survival rate, recent change in five-year survival (1999-2006 vs 1990-1992), and five-year mortality estimate (=annual incidence*[1 - 5-yr survival rate]). In 2011, the authors identified 231 active clinical trials for therapeutic cancer vaccines. Of these trials, 81 vaccines are currently in Phase I, 140 in Phase II, and 10 vaccines in Phase III. Vaccine trials for melanoma are most common (n=40), followed by breast cancer (34), lung cancer (30), and prostate cancer (22). Correlation analyses revealed that only annual cancer incidence is significantly associated with current therapeutic cancer vaccine trial activity (r=.60; p=.003). Annual mortality, 5-year survival rate and 5-year mortality estimates were not associated with vaccine trial activity. The authors conclude that therapeutic cancer vaccine clinical trials correspond with disease incidence in the U.S., but not with measures of mortality and survival that reflect the effectiveness of currently available treatment modalities. Future development of therapeutic vaccines for cancer may benefit patients more if there is stronger complementarity with other therapeutic options.
cancer; clinical trials; immunotherapy; incidence; mortality; vaccine
To evaluate the general safety of zoster vaccine (ZV) in adults ≥60 years old.
Subjects were enrolled in a 1:1 ratio to receive 1 dose of ZV or placebo. Subjects were followed for serious adverse experiences (SAEs) for 42 days (primary follow-up period) and 182 days (secondary follow-up period) postvaccination. Relative-risks (ZV/placebo) for SAEs during both safety periods were calculated. Study period: 17-Sep‑2007 to 09-Jan-2009.
Overall, 5,983 subjects received ZV and 5,997 received placebo. Within the primary 42-day follow-up period, 84 ZV subjects and 67 placebo subjects reported SAEs. The estimated risk of SAEs within 42 days was 1.41% for ZV versus 1.12% for placebo, with a relative-risk of 1.26 (95% CI 0.91,1.73); indicating no statistically significant difference between groups, meeting the pre-specified success criterion. During the 182-day follow-up period, 340 ZV subjects and 300 placebo subjects reported SAEs. The estimated risk of SAEs within 182 days was 5.68% for ZV versus 5.01% for placebo, with a relative-risk of 1.13 (95% CI 0.98,1.32), indicating no statistically significant difference between groups. Two subjects in the ZV group reported SAEs deemed by the investigator to be vaccine-related (uveitis and sciatica; onset Day 5 and 4, respectively). One subject in the placebo group reported a SAE deemed by the investigator to be vaccine-related (lumbar radiculopathy; onset Day 51). There were 24 fatal SAEs in the ZV group and 17 in the placebo group (relative risk = 1.41; CI: 0.77, 2.60); 6 and 5, respectively, with SAE onset during the primary 42-day follow-up period. No deaths were deemed vaccine-related.
ZV and placebo groups had similar safety profiles in terms of SAEs during the primary (Day 1 to 42) and secondary (Day 1 to 182) follow-up periods.
clinical study; herpes zoster; safety; tolerability; zoster vaccine
Objective: This study examined changes in parental influenza vaccination attitudes and intentions after participating in school-based educational influenza vaccination intervention. Methods: Participants were drawn from three counties participating in a school-based influenza vaccination intervention in rural Georgia (baseline N=324; follow-up N=327). Data were collected pre- and post-intervention from phone surveys with parents’ with children attending middle- and high-school. Attitudes, beliefs, vaccination history, and intention to vaccinate were assessed. Results: Parents who participated in the intervention conditions reported significantly higher influenza vaccination rates in their adolescents, relative to a control group, as well as increased vaccination rates post-intervention participation relative to their baseline rates. Intervention participants reported greater intention to have their adolescent vaccinated in the coming year compared to control parents. Significant differences were observed post intervention in perceived barriers and benefits of vaccination. Conclusions: These findings suggest that a school- educational influenza vaccination intervention targeting parents and teens may influence influenza vaccination in rural communities. Future influenza vaccination efforts geared toward the parents of rural middle- and high-school students may benefit from addressing barriers and benefits of influenza vaccination.
Adolescents; attitudes; school-based; seasonal influenza; vaccination
Prevalence rates for leprosy have declined sharply over the past 20 y, with this decline generally attributed to the WHO multi-drug therapy (MDT) campaign to provide free-of-charge treatment to all diagnosed leprosy patients. The success of this program appears to have reached its nadir, however, as evidenced by the stalled decreases in both global prevalence and new case detection rates of leprosy. Mass BCG vaccination for the prevention of tuberculosis (TB) at national levels has had a positive effect on leprosy decline and is often overlooked as an important factor in current leprosy control programs. Because BCG provides incomplete protection against both TB and leprosy, newer more effective TB vaccines are being developed. The impact that application of these vaccines will have on current leprosy control programs is unclear. In this review, we assess the need for vaccines within leprosy control programs. We summarize and discuss leprosy vaccine strategies that have been deployed previously and discuss those strategies that are currently being developed to augment recent breakthroughs in leprosy control.
leprosy; mycobacteria; T cell; vaccine
Schistosomiasis is a major neglected tropical disease of public health importance to a billion people. An estimated 200 million people are currently infected; an additional 779 million individuals are at risk to acquire the infection in 74 countries. Despite many years of implementation of mass anti-parasitic drug therapy programs and other control measures, this disease has not been contained and continues to spread to new geographic areas. The discovery of a protective vaccine still remains the most potentially effective means for the control of this disease, especially if the vaccine provides long-term immunity against the infection. A vaccine would contribute to the reduction of schistosomiasis morbidity through induced immune responses leading to decrease in parasite load and reduced egg production. This vaccine could be administered to children between the ages of 3 and 12 years to prevent severe infection in a particularly high risk population. This review summarizes the current status of schistosomiasis vaccine development.
calpain; neglected tropical disease (NTD); protective immunity; Schistosomiasis; Sm-p80; vaccines
The human hookworms Necator americanus and Ancylostoma duodenale remain among the most common infections of humans in areas of rural poverty in the developing regions of the world, with an estimated 1 billion people infected with one or more of these parasites. Herein, we review the nearly 100 years of research, development, animal testing, and fieldwork that have led to our current progress in recombinant hookworm vaccines. We begin with the identification of hookworm at the start of the 20th century in Southern US, then discuss the progress in developed countries to eliminate human hookworm infection, and then the industrial development and field use in the 1970s a canine hookworm vaccine(Ancylostoma caninum), and finally our progress to date in the development and clinical testing of an array of recombinant antigens to prevent human hookworm disease from N. americanus infection. Special attention is given to the challenges faced in the development of a vaccine against a blood-feeding nematode, including the epidemiology of infection (high prevalence of infection), pathogenesis (chronic infection that increases with the age of the host), and a robust immune response that fails to confer the protection in the host and a concomitant absence of correlates of protection by a successful vaccine could be developed and tested. Finally, we provide the optimal and acceptable profiles of a human hookworm vaccine, including the proposed indication, target population, and route of administration, as developed by the Human Hookworm Vaccine Initiative, the only group currently working on vaccines targeting this parasite.
Helicobacter pylori was appreciated as the major cause of peptic ulcers about 30 y ago and the most significant etiological agent in gastric cancer in the mid-1990s. Since that time, progress in the development of a preventive or therapeutic H. pylori vaccine has been relatively slow. The impediments to rapid advances in the field include a luke-warm enthusiasm among clinicians, research scientists, and public health authorities concerning the need for a vaccine, rudimentary understanding of the correlates of gastric immunity to H. pylori and of gastric mucosal immunology in general, the geographical heterogeneity of the H. pylori genome and insufficient pharmaceutical industry support. Recent enhancements in our understanding of the gastric immune response together with advances in H. pylori genomics now provide the potential to accelerate progress in H. pylori vaccine development. Whether an H. pylori vaccine becomes a reality will likely depend upon our ability to appropriately target the populations at highest risk of the adverse sequelae of infection.
gastritis; gastric cancer; Helicobacter pylori; vaccination; gastric immunity
Infections with Pseudomonas aeruginosa are a major health problem for immune-compromised patients and individuals with cystic fibrosis. A vaccine against P. aeruginosa has long been sought after, but is so far not available. Several vaccine candidates have been assessed in experimental animals and humans, which include sub-cellular fractions, capsule components, purified and recombinant proteins. Unique characteristics of the host and the pathogen have complicated the vaccine development. This review summarizes the current state of vaccine development for this ubiquitous pathogen, in particular to provide mucosal immunity against infections of the respiratory tract in susceptible individuals with cystic fibrosis.
Pseudomonas aeruginosa; vaccines; Pseudomonas antigens; cystic fibrosis; adenovirus
Tumors stimulate angiogenesis to meet increasing nutrient and oxygen demands. In addition to their role in vascular remodeling, pro-angiogenic cytokines and effector cells contribute to an immune-inhibitory environment associated with advanced malignancies. Despite the critical role of angiogenesis in tumor growth and dissemination, most anti-angiogenic cancer therapies have had only limited success selectively targeting one of the many factors implicated in this process. Similarly, the effectiveness of tumor immunotherapies has been limited by tumor-mediated escape mechanisms and immune suppression. By combining the two strategies, however, anti-angiogenic immunotherapy offers the possibility to more robustly inhibit tumor angiogenesis and simultaneously impact the immune-inhibitory effects of the pro-angiogenic tumor milieu. These potential synergies make the combination of immunotherapy and anti-angiogenic treatment a promising avenue for future research.
angiogenesis; vaccine; immunotherapy; GM-CSF; angiopoietin
We characterized parental attitudes regarding school HPV vaccination requirements for adolescent girls. Study participants were 866 parents of 10–18 y-old girls in areas of North Carolina with elevated cervical cancer incidence. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression. Approximately half (47%) of parents agreed that laws requiring HPV immunization for school attendance “are a good idea” when opt-out provisions were not mentioned. Far more agreed that “these laws are okay only if parents can opt out if they want to” (84%). Predictors of supporting requirements included believing HPV vaccine is highly effective against cervical cancer (OR = 2.5, 95% CI:1.7–5.0) or is more beneficial if provided at an earlier age (OR = 16.1, 95% CI:8.4–31.0). Parents were less likely to agree with vaccine requirements being a good idea if they expressed concerns related to HPV vaccine safety (OR = 0.3, 95% CI:0.1–0.5), its recent introduction (OR = 0.3, 95% CI:0.2–0.6). Parental acceptance of school requirements appears to depend on perceived HPV vaccine safety and efficacy, understanding of the optimal age for vaccine administration, and inclusion of opt-out provisions.
Public policy; human papillomavirus; cervical cancer; vaccine; mandates; requirements; implementation
Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16–26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2 and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs. 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs. 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16–26 years and had a favorable safety profile.
human papillomavirus (HPV); vaccine; safety; male; adult; adolescent
To develop a survey to accurately assess parental vaccine hesitancy.
The initial survey contained 17 items in four content domains: (1) immunization behavior; (2) beliefs about vaccine safety and efficacy; (3) attitudes about vaccine mandates and exemptions; and (4) trust. Focus group data yielded an additional 10 survey items. Expert review of the survey resulted in the deletion of nine of 27 items and revisions to 11 of the remaining 18 survey items. Parent pretesting resulted in the deletion of one item, the addition of one item, the revision of four items, and formatting changes to enhance usability. The final survey contains 18 items in the original four content domains.
An iterative process was used to develop the survey. First, we reviewed previous studies and surveys on parental health beliefs regarding vaccination to develop content domains and draft initial survey items. Focus groups of parents and pediatricians generated additional themes and survey items. Six immunization experts reviewed the items in the resulting draft survey and ranked them on a 1–5 scale for significance in identifying vaccine-hesitant parents (5 indicative of a highly significant item). The lowest third of ranked items were dropped. The revised survey was pretested with 25 parents to assess face validity, usability and item understandability.
The Parent Attitudes about Childhood Vaccines survey was constructed using qualitative methodology to identify vaccine-hesitant parents and has content and face validity. Further psychometric testing is needed.
pediatrics; vaccination; public health practice; preventive health services; questionnaires
Expression of recombinant vaccine antigens and monoclonal antibodies using plant viral vectors has developed extensively during the past several years. The approach benefits from high yields of recombinant protein obtained within days after transient delivery of viral vectors to leaves of Nicotiana benthamiana, a tobacco relative. Modified viral genomes of both RNA and DNA viruses have been created. Geminiviruses such as bean yellow dwarf virus (BeYDV) have a small, single stranded DNA genome that replicates in the nucleus of an infected plant cell, using the cellular DNA synthesis apparatus and a virus-encoded replication initiator protein (Rep). BeYDV-derived expression vectors contain deletions of the viral genes encoding coat and movement proteins and insertion of an expression cassette for a protein of interest. Delivery of the geminiviral vector to leaf cells via Agrobacterium-mediated delivery produces very high levels of recombinant DNA that can act as a transcription template, yielding high levels of mRNA for the protein of interest. Several vaccine antigens, including Norwalk virus capsid protein and hepatitis B core antigen, were expressed using the BeYDV vector at levels up to 1 mg per g of leaf mass. BeYDV replicons can be stacked in the same vector molecule by linking them in tandem, which enables production of multi-subunit proteins like monoclonal antibody (mAb) heavy and light chains. The protective mAb 6D8 against Ebola virus was produced at 0.5 mg per g of leaf mass. Multi-replicon vectors could be conveniently used to produce protein complexes, e.g., virus-like particles that require two or more subunits.
bean yellow dwarf virus; geminiviral replicon; monoclonal antibody; plant-derived vaccine; vaccine; virus-like particle
vaccines; monoclonal; antibodies; plant; GMP; rabies; immune complex; intellectual property
vaccine; adjuvant conference; HIV; immunity
Neisseria meningitidis is a major cause of invasive bacterial infections worldwide. For this reason, efforts to control the disease have been directed at optimizing meningococcal vaccines and implementing appropriate vaccination policies. In the past, plain polysaccharide vaccines containing purified capsular polysaccharides A, C, Y and W135 were developed, but failed to protect infants, who are at greatest risk.
Experience with the conjugate Haemophilus vaccine suggested that this approach might well empower meningococcal vaccines. Thus, a very efficacious vaccine against serogroup C Neisseria meningitidis was optimized and has been widely used in developed nations since 1999.
On the basis of epidemiological changes in the circulation of pathogenic serogroups in the United States, a quadrivalent conjugate vaccine against A, C, Y and W135 serogroups (Menactra™) has been developed and was approved by the US FDA (Food and Drug Administration) in 2005. Recently, another tetravalent conjugate meningococcal vaccine (Menveo™) has been licensed and made available in the United States of America and in the European Union.
Finally, in response to large epidemics caused by serogroup A meningococcus in Africa, a new, safe, immunogenic and affordable vaccine has been developed.
This review highlights the evolution of conjugate meningococcal vaccines in general and discusses how this kind of vaccine can contribute to preventing meningococcal disease.
meningococcus; Neisseria meningitidis; glycoconjugate vaccines; meningococcal disease; immunity; vaccination
Adolescent human papillomavirus (HPV) vaccination uptake, as a means of cervical cancer prevention, remains suboptimal with significant racial disparity. A survey study of mothers already engaging in their own cancer screening, at a predominantly black urban site and a predominantly white suburban site, finds that a majority of mothers surveyed support hypothetical mandates for adolescent HPV vaccination three years after the introduction of these vaccines. Enactment of state laws may represent an efficient means to improve HPV vaccination in adolescent daughters of these mothers. Nevertheless, in a sizable minority, maternal perceptions of the HPV vaccine may hinder adherence to these vaccination laws. In these women, tailored interventions directed at these perceptions may be required.
mandates; maternal barriers; health behavior; legislation; teachable moment
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease resulting in the destruction of the insulin-secreting β cells. Currently, there is no established clinical approach to effectively suppress long-term the diabetogenic response. Genetic-based vaccination offers a general strategy to reestablish β cell-specific tolerance within the T cell compartment. The transfer of genes encoding β cell autoantigens, anti-inflammatory cytokines and/or immunomodulatory proteins has proven to be effective at preventing and suppressing the diabetogenic response in animal models of T1D. The current review will discuss genetic approaches to prevent and treat T1D with an emphasis on plasmid DNA- and adeno-associated virus-based vaccines.
immunoregulation; gene transfer; autoimmunity; plasmid DNA; viral vectors
Immunization is a successful and cost-effective method for preventing disease, yet many adolescents do not receive recommended vaccines. We assessed correlates of uptake of three vaccines (tetanus booster, meningococcal and human papillomavirus [HPV] vaccines) recommended for adolescent females.
Only 17% of parents indicated their daughters had received all three vaccines. Eighty-seven percent of parents indicated their daughters had received tetanus booster vaccine, 36% reported vaccination against meningococcal disease and 36% reported HPV vaccine initiation. Daughters aged 13–15 years (OR = 1.70, 95% CI: 1.09–2.64) or 16–20 years (OR = 2.28, 95% CI: 1.51–3.44) had received a greater number of these vaccines compared to daughters aged 11–12 years. Daughters who had preventive care visits in the last year (OR = 4.81, 95% CI: 3.14–7.34) or whose parents had at least some college education (OR = 1.90, 95% CI: 1.29–2.80) had also received a greater number of these vaccines.
We examined cross-sectional data from 647 parents of 11–20 year-old females from North Carolina who completed the Carolina HPV Immunization Measurement and Evaluation (CHIME) Project follow-up survey in late 2008. Analyses used ordinal and binary logistic regression.
Few daughters, particularly 11–12 years olds, had received all three vaccines recommended for adolescent females. Ensuring annual preventive care visits and increasing concomitant administration of adolescent vaccines may help increase vaccine coverage.
vaccine; adolescents; HPV; meningitis; tetanus; pertussis; diphtheria
An outer membrane protein (OMP) of nontypeable Haemophilus influenzae (NTHi), P6, is a vaccine candidate because it has been characterized as conserved among all H. influenzae strains. Among 151 isolates from children, age 6 to 30 months, evaluating NTHi nasopharyngeal (NP) and oropharyngeal (OP) colonization and tympanocentesis confirmed acute otitis media we identified 14 strains (9.3%) that had variant protein sequences of P6. One atypical omp P6 isolate had sequence mutations in the binding site of a proposed major antigenic epitope of omp P6 identified by monoclonal antibody 7F3. Eight strains (5.3%) had non-homologous variations in amino acids that could result in significant changes to the protein structure of P6, and 5 other strains had amino acid substitutions at four previously described key residue sites. These results show that NTHi omp P6 is not invariant in its structure among respiratory isolates from children.
acute otitis media; P6 protein; nasopharyngeal; H. influenza
During the 2009 H1N1 influenza pandemic nearly every decision associated with new vaccine development and dissemination occurred from the Spring of 2009, when the novel virus first emerged, to the Fall of 2009, when the new vaccines started reaching the thighs, arms and noses of vaccinees. In many ways, 2009 served as a crash course on how mathematical and computational modeling can assist all aspects of vaccine decision-making. Modeling influenced pandemic vaccine decision-making, but not to its fullest potential. The 2009 H1N1 pandemic demonstrated that modeling can help answer questions about new vaccine development, distribution, and administration such as (1) is a vaccine needed, (2) what characteristics should the vaccine have, (3) how should the vaccine be distributed, (4) who should receive the vaccine and in what order and (5) when should vaccination be discontinued? There is no need to wait for another pandemic to enhance the role of modeling, as new vaccine candidates for a variety of infectious diseases are emerging every year. Greater communication between decision makers and modelers can expand the use of modeling in vaccine decision-making to the benefit of all vaccine stakeholders and health around the globe.
influenza; H1N1; vaccine; modeling; pandemic; vaccine development; vaccine distribution; vaccine administration
A bivalent factor H binding protein (fHBP) vaccine for the prevention of disease caused by Neisseria meningitidis serogroup B is currently in clinical development. Since fHBP is also expressed by other meningococcal serogroups, antifHBP antibodies may have bactericidal activity against meningococci independent of serogroup. To begin examining the susceptibility of other meningococcal serogroups to anti-fHBP antibodies, meningococcal serogroup C invasive isolates (n = 116) were collected from the Centers for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) sites during 2000–2001. These isolates were analyzed for the presence of the fhbp gene. All serogroup C isolates contained the gene, and sequence analysis grouped the proteins into two subfamilies, A and B. Flow cytometry analysis demonstrated that fHBP was expressed on the surface of ∼70% of isolates in vitro with varying levels of expression. fHBP was accessible to antibodies on the cell surface even in the presence of the polysaccharide capsule. Nine isolates from different geographic regions were identified which harboured an identical single nucleotide deletion that could result in a truncated subfamily B fHBP. Analysis by flow cytometry using a polyclonal fHBP antibody preparation revealed that a subpopulation of each of these isolates expressed fHBP. rabbit and non-human primate immune sera generated with bivalent fHBP vaccine were tested for bactericidal activity against a panel of diverse serogroup C clinical isolates using human complement. Sera from both species demonstrated serum bactericidal antibody activity against the serogroup C isolates tested. These promising findings suggest that a bivalent fHBP vaccine may be capable of providing protection against meningococcal disease caused by both serogroup C and B.
Neisseria meningitidis serogroup C; vaccine; fHBP
vaccine; diabetes; dendritic cell; microparticle; microsphere; immunotherapy