Table of Contents

Volume 8, Issue 6

  June 2012

  Pages 695 - 844

View covers archive

 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Letter from the Editor

Ronald W. Ellis and Eva M. Riedmann
Page 695
http://dx.doi.org/10.4161/hv.21031
PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 696 - 699
http://dx.doi.org/10.4161/hv.21034
Abstract | PDF

Agenus`Prophage brain cancer vaccine shows promise in phase 2
New insights into how RV144 vaccine may have protected against HIV
Positive interim results from phase I/II multiple myeloma cancer vaccine trial
European authorisation for GSK's quadrivalent meningococcal vaccine Nimenrix
Sanofi presents pediatric data on investigational quadrivalent influenza vaccine
Phase 3 trial for PROSTVAC starts in Europe 
For better results: immunize men in the morning and women in the afternoon
Nearly 300 vaccines in R&D

Open Access Article

Profile: PATH’s Vaccine Development Global Program

John W. Boslego
Pages 700 - 701
http://dx.doi.org/10.4161/hv.21033
PDF




PORTRAIT OF A LEADING VACCINOLOGIST

Vaccines and public policy

William Schaffner
Pages 702 - 705
http://dx.doi.org/10.4161/hv.21037
Abstract | PDF

My commitment to vaccines had its beginnings in an unlikely fashion. I just had completed two years of an internal medicine residency as well as two years of clinical and research training in infectious diseases at Vanderbilt University Medical Center in Nashville, Tennessee. Now it was time to fulfill my national service obligation (Selective Service—“the draft”) that all young men had back in the 1960s. Because of my interest in infectious diseases, it had been suggested that, rather than serving in the Army, I apply for a Commission in the US Public Health Service. To my delight and considerable surprise I had been accepted and I reported for training and further assignment to the Communicable Disease Center in Atlanta (now the Centers for Disease Control and Prevention—CDC) as a newly minted Epidemic Intelligence Service (EIS) Officer. Under the stern guidance of Alexander Langmuir, CDC’s chief epidemiologist, each cadre of novice EIS Officers were immersed in the principles and practice of investigative field epidemiology which transformed clinicians such as myself who had heretofore focused on the illnesses of single patients into public health physicians who worked to ensure the health of entire communities. The 6-week instruction period was both demanding and inspiring. It instilled an esprit de corps; and at the completion of our training we were eager to undertake our new roles as “disease detectives” in our duty assignments. Mine was to be at the state health department in Rhode Island. Which is where I encountered measles and measles vaccine.




REVIEW

Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy?

Christopher J.A. Duncan, Adrian V.S. Hill and Ruth D. Ellis
Pages 706 - 714
http://dx.doi.org/10.4161/hv.19712
Abstract | Full Text | PDF

An effective vaccine against P. falciparum malaria remains a global health priority. Blood-stage vaccines are an important component of this effort, with some indications of recent progress. However only a fraction of potential blood-stage antigens have been tested, highlighting a critical need for efficient down-selection strategies. Functional in vitro assays such as the growth/invasion inhibition assays (GIA) are widely used, but it is unclear whether GIA activity correlates with protection or predicts vaccine efficacy. While preliminary data in controlled human malaria infection (CHMI) studies indicate a possible association between in vitro and in vivo parasite growth rates, there have been conflicting results of immunoepidemiology studies, where associations with exposure rather than protection have been observed. In addition, GIA-interfering antibodies in vaccinated individuals from endemic regions may limit assay sensitivity in heavily malaria-exposed populations. More work is needed to establish the utility of GIA for blood-stage vaccine development.




PRODUCT REVIEW

Development of a group A meningococcal conjugate vaccine, MenAfriVac^TM

Carl E. Frasch, Marie-Pierre Preziosi and F. Marc LaForce
Pages 715 - 724
http://dx.doi.org/10.4161/hv.19619
Abstract | PDF

Group A meningococcal disease has been an important public health problem in sub-Saharan Africa for over a century. Outbreaks occur there annually, and large epidemics occur at intervals ranging between 8 and 12 y. The Meningitis Vaccine Project was established in 2001 with funding from the Gates Foundation with the goal of developing, testing, licensing, and introducing an affordable group A meningococcal conjugate vaccine into Africa. From 2003 to 2009 a monovalent group A conjugate vaccine, MenAfriVac^TM, was developed at the Serum Institute of India, Ltd through an innovative public/private partnership. Preclinical studies of the new conjugate vaccine were completed in 2004 and a Phase 1 study began in India in 2005. Phase 2/3 studies in African 1–29 y olds were completed in 2009 showing the new meningococcal A conjugate vaccine to be as safe as currently licensed meningococcal polysaccharide vaccines, but much more immunogenic. After Indian market authorization (December 2009) and WHO prequalification (June 2010), MenAfriVac^TM was introduced at public health scale using a single 10 µg dose in individuals 1–29 y of age in Burkina Faso, Mali, and Niger in December 2010. We summarize the laboratory and clinical studies leading to prequalification of MenAfriVac^TM. The 2011 epidemic season ended with no reported case of group A meningitis in vaccinated individuals.




RESEARCH PAPERS

Dynamics of the antibodies in cohorts of cured cases of visceral leishmaniasis: Its implication on the validity of serological test, value in prognosis and in post therapeutic assessment

Rajan R. Patil, Jayaparakash Muliyil, Nandy A, Addy A, Maji AK and Prabir Chatterjee
Pages 725 - 730
http://dx.doi.org/10.4161/hv.19542
Abstract | PDF

The major disadvantage of a Serological test like Direct Agglutination Test (DAT) for Visceral Leishmaniasis (also called Kala-azar) is its inability to distinguish between recent and past infection. The objective of our study was to look at rate of decline of antibodies in fully cured cases of Kala-azar and length of time it takes for DAT to become negative. Cohort Study involving completely treated Kala-azar cases from Government Hospital during one calendar year of study. Cases were selected on the basis of treatment cohorts 0,3,6,9 &12 mo after completion of treatment.. Phase I- The cases were traced and after obtaining the informed consent they were subjected to Direct Agglutination Test (DAT). Phase II-The five treatment cohorts, constituting 82 cured cases (average of 15 cured cases per each treatment cohort) were tested again with DAT three months after the first test. The titers of Phase-I and phase-II tests were analyzed for the dynamics of the antibodies for the period. Cutoff- Values of DAT below 1:800 are considered negative. Values of 1:800, 1:1200, 1:1600 and so on are considered positive. The mean titer [Geometric Mean Titer (GMT)] at the start of treatment was 1:1120, which showed steady decline up to six months, plummeting below the cutoff titer for the DAT (1:800) at the ninth month. Antibodies continue to linger for about one year in cured Kala-azar cases even after correct and complete treatment. Single DAT results may be misleading due to high false positivity up to one year after the cure. Paired test defined as two tests 3 mo apart on the same subject. Paired test is highly recommended for diagnosis and prognosis. DAT is still a very useful tool for diagnosis if used along with clinical correlation

Mandatory influenza vaccination programs for health care personnel in NACHRI-associated children’s hospitals vs. non-children’s hospitals

Phoebe Danziger and Matthew M. Davis
Pages 731 - 735
http://dx.doi.org/10.4161/hv.19613
Abstract | PDF

We conducted a national study of children’s hospitals and neighboring general medical-surgical hospitals to examine their employee vaccination policies. Survey questions addressed health care personnel (HCP) influenza vaccination policies for the 2009–2010 (seasonal, H1N1) and 2010–2011 (H1N1+seasonal = combined) influenza seasons at each hospital, assessment of primary objectives behind hospitals’ influenza vaccination policies, and information about influenza vaccination policies for inpatient children. We conducted standard univariate and bivariate statistical analyses. The study sample included 136 hospitals: 71 children’s hospitals (response rate = 59%) and 65 matched non-children’s hospitals (39%). Children’s hospitals were significantly more likely than non-children’s institutions to have mandatory H1N1 influenza vaccination policies for their HCP in 2009–10 (27% vs. 13%, p = 0.03). There were no differences in HCP influenza vaccination policies otherwise: 25% in both groups with mandatory seasonal vaccination programs in 2009–10, and 19% in both groups with mandatory combined influenza programs in 2010–11. Children’s hospitals were significantly more likely to have policies in place strongly encouraging inpatient children to have influenza vaccination than were non-children’s hospitals (47% vs 5%; p < 0.001). Among children’s and non-children’s hospitals alike, the primary intentions of HCP influenza vaccination policies were to reduce transmission of influenza from employees to patients (89% overall) and to reduce transmission of influenza from patients to employees (70%). This study—the first known national assessment of hospitals’ policies regarding influenza—suggests that HCP mandatory vaccination is uncommon, even in child-focused hospitals where the patient population is known to be at disproportionately high risk for complications from the illness.

Antibody persistence after two vaccinations with either FSME-IMMUN® Junior or ENCEPUR® Children followed by third vaccination with FSME-IMMUN® Junior

Roman Prymula, Eva Maria Pöllabauer, Borislava G. Pavlova, Alexandra Löw-Baselli, Sandor Fritsch, Rudolf Angermayr, Alexander Geisberger, P. Noel Barrett and Hartmut J. Ehrlich
Pages 736 - 742
http://dx.doi.org/10.4161/hv.20058
Abstract | Full Text | PDF

Tick-borne encephalitis (TBE) vaccination strategies to induce optimal seroprotection in children are under constant evaluation. This multi-center, randomized, controlled, phase III clinical study examined antibody persistence in children aged 1–11 y following two prospectively administered doses of either the FSME-IMMUN® Junior or Encepur Children® vaccines, as well as investigating the immunogenicity, safety and vaccine interchangeability of a third vaccination with FSME-IMMUN^® Junior. A high level of antibody persistence was observed in all subjects 6 mo after the first of two vaccinations with either pediatric TBE vaccine. Based on both immunological tests and viral antigens used, slightly higher seropositivity rates and higher GMCs /GMTs were found in children vaccinated with FSME-IMMUN® Junior compared with those who received Encepur® Children. Seropositivity rates across all age strata combined six months after the first vaccination with FSME-IMMUN® 0.25 mL Junior were 95.1% as determined by Immunozym ELISA, 93.2% as determined by Enzygnost ELISA and 95.3% as determined by NT; compared with 62.6%, 80.5% and 91.0% respectively after vaccination with Encepur® Children. A third vaccination with FSME-IMMUN^® Junior induced 100% seropositivity in both study groups and was well tolerated as demonstrated by the low rates of systemic and injection site reactions. Subjects who received either FSME-IMMUN Junior® or Encepur^® Children vaccine for the first two vaccinations and FSME-IMMUN Junior® for the third showed a comparably strong immune response regardless of the previous TBE vaccine administered, demonstrating that two vaccinations with Encepur® Children can successfully be followed by a third vaccination with FSME-IMMUN Junior®.

Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in the Netherlands

Jane Whelan, Susan Hahné, Guy Berbers, Fiona R.M. van der Klis, Yvonne Wijnands and Hein Boot
Pages 743 - 748
http://dx.doi.org/10.4161/hv.19642
Abstract | PDF

The hexavalent vaccine Infanrix hexa was introduced into the national childhood vaccination schedule in the Netherlands in 2006. It is offered, concomitantly with pneumococcal vaccine (Prevenar), to children at increased risk of hepatitis B, administered in a 4-dose schedule at 2, 3, 4 and 11 months of age. We assessed the immunogenicity of the HBV component of Infanrix hexa co-administered with Prevenar, and compared pertussis and Hib components in Infanrix hexa with the standard Infanrix-IPV+Hib vaccine. Target thresholds for immune responses were achieved for all antigens studied. Over 99% (163/164) of children vaccinated with Infanrix hexa achieved an adequate immune response (³10 mIU/ml) to the HBV component and peak anti-HBs geometric mean concentration (GMC) was 2264mIU/ml (95%CI:1850-2771mIU/ml). The GMC of a pertussis component, filamentous hemagglutinin (FHA), of Infanrix-hexa was significantly lower in children vaccinated with Infanrix hexa and Prevenar than in children vaccinated with Infanrix-IPV+Hib. Universal infant HBV vaccination using Infanrix hexa was introduced in the Netherlands in 2011. Despite very high rates of seroconversion for the HBV component of Infanrix hexa, its long term immunogenicity and effectiveness should be monitored after concomitant vaccination.

Safety and persistence of immunological response 6 months after intramuscular vaccination with an AS03-adjuvanted H1N1 2009 influenza vaccine: An open-label, randomized trial in Japanese children aged 6 months to 17 years

Akihiko Saitoh, Akira Nagai, Kazuyoshi Tenjinbaru, Ping Li, François Roman and Tatsuo Kato
Pages 749 - 758
http://dx.doi.org/10.4161/hv.19684
Abstract | Full Text | PDF

This study evaluated the long-term persistence of immune response and safety of two doses of an A/California/7/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) in Japanese children (NCT01001169). Sixty healthy subjects aged 6 mo−17 y were enrolled (1:1) into two study groups to receive 21 d apart, two doses of 1.9µg haemagglutinin [HA]+AS03_B (5.93mg α-tocopherol) vaccine (6 mo−9 y) and 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine (10–17 y), respectively. Immunogenicity data (by haemagglutination inhibition [HI] and microneutralisation assays) to six months after the first vaccine dose are reported here. It was observed that following Dose 2, the HI immune response against the vaccine homologous strain induced by the two different dosages of the AS03-adjuvanted vaccine met and exceeded the US and European regulatory guidance criteria for pandemic influenza vaccines (seroprotection rate[SPR]/seroconversion rate[SCR]: 100%/100%; geometric mean fold rise GMFR: 146.8/57.1). Further, the immune response persisted for at least six months after the first vaccine dose wherein these regulatory criteria were still met (SPR: 100%/100%; SCR: 96.4%/89.7%; GMFR: 25.3/23.5). The neutralising antibody response was comparable to the HI immune response at Day 42 (vaccine response rate [VRR]: 100%/100%) and at Day 182 (VRR: 96.4%/82.8%). Overall, both vaccine dosages had a clinically acceptable safety profile. Thus, two doses of a 1.9µg or 3.75µg HA AS03-adjuvanted H1N1 2009 pandemic influenza vaccine in children aged 6 mo−17 y induced strong immune responses against the vaccine homologous strain that persisted for at least six months after the first vaccine dose.

Filterable forms and L-forms of Mycobacterium bovis BCG: Impact for live vaccine features

Nadya Markova, Georgi Slavchev and Lilia Michailova
Pages 759 - 764
http://dx.doi.org/10.4161/hv.19698
Abstract | Full Text | PDF

Bacterial L-form conversion, or existence without cell walls, is assumed a universal phenomenon in nature. An interesting aspect of this phenomenon is occurrence of L-forms in vaccine strains. Since BCG is currently a widely used and extensively studied live vaccine for tuberculosis, understanding L-form conversion of M. bovis BCG bacilli can provide new insight into behavior of BCG vaccine. In this respect, specific features, concerning the ability of BCG vaccine to produce viable filterable forms and L-forms, were studied by filtration and starvation stress experiments in vitro. The filterable forms obtained after filtration of BCG suspension, grew on Middlebrook 7H9 semisolid agar and formed typical “fried eggs” L-form colonies. Electron microscopy clearly demonstrated presence of L-form elements with size smaller than the size of bacterial filter pores of 0.2 µm in M. bovis BCG strains. Development of L-form subpopulation with typical morphological appearance of self-replicating cell wall-defective forms was observed after filtration, as well as after starvation stress. Specific DNA detection of pncA gene in derived L-form cultures from filterable and stressed BCG strains verified their identity as M. bovis BCG. In conclusion, the results confirm existence of filterable forms in commercial BCG vaccine, which are able to develop L-form population under appropriate conditions. L-form transformation of BCG bacilli displays a new intriguing aspect concerning exhibition of unusual features and atypical behavior of live BCG vaccine. Further research is requested to explore the influence of L-form phenomenon on BCG vaccine effects in vivo

Advances in vaccines against neglected tropical diseases: Enhancing physical stability of a recombinant hookworm vaccine through biophysical and formulation studies

Jordan Plieskatt, Wanderson Rezende, Chris Olsen, Jared Trefethen, Sangeeta B. Joshi, C. Russell Middaugh, Peter J. Hotez and Maria Elena Bottazzi
Pages 765 - 776
http://dx.doi.org/10.4161/hv.19726
Abstract | Full Text | PDF

A bivalent recombinant vaccine for human hookworm disease is under development. One of the lead candidate antigens in the vaccine is a glutathione S-transferase cloned from the hookworm Necator americanus (Na-GST-1) which is expressed in the yeast Pichia pastoris. Based on preliminary studies demonstrating that the recombinant protein was not stable in an acetate buffer at pH 6, we undertook an extensive stability analysis of the molecule. To improve and optimize stability we complemented traditional methods employed for macromolecule and vaccine stabilization with biophysical techniques that were incorporated into a systematic process based on an eigenvector approach. Large data sets, obtained from a variety of experimental methods were used to establish a color map (“empirical phase diagram”) of the physical stability of the vaccine antigen over a wide range of temperature and pH. The resulting map defined “apparent phase boundaries” that were used to develop high throughput screening assays. These assays were then employed to identify excipients that stabilized the antigen against physical degradation that could otherwise result in losses of physicochemical integrity, immunogenicity, and potency of the vaccine. Based on these evaluations, the recombinant Na-GST-1 antigen was reformulated and ultimately produced under Good Manufacturing Practices and with an acceptable stability profile.

Evaluating the health impact of a public-private partnership: to reduce rotavirus disease in Nicaragua

Shazia S. Khawaja, Anna Cardellino, Diana Klotz, Barbara J. Kuter, Mark Feinberg, Brenda Colatrella and T. Christopher Mast
Pages 777 - 782
http://dx.doi.org/10.4161/hv.19757
Abstract | Full Text | PDF

The purpose of this article is to describe the RotaTeq^® Nicaragua Partnership and the evaluation of the public health impact of the vaccine conducted by the partners, including the creation of a rotavirus surveillance program and a vaccine effectiveness assessment. The three main objectives of the partnership were to demonstrate that a new rotavirus vaccine could (1) be introduced rapidly in a developing country, (2) be successfully integrated into the existing vaccine delivery infrastructure, and (3) have a significant and measurable public health impact at the end of the 3-y program. The vaccine impact assessment required collaboration among partners with different areas of expertise, including the Nicaraguan Ministry of Health, Merck, local hospitals, government health clinics, laboratories, and a Technical Advisory Group. Through the partnership, RotaTeq^® became available in a GAVI-eligible developing country, Nicaragua, in the same year it was approved in the United States. Vaccine coverage rapidly reached over > 90% of eligible Nicaraguan children. The impact assessment evaluated over 10,000 subjects and leveraged and enhanced the existing diarrheal surveillance infrastructure, ultimately providing the scientific community with some of the first real-world rotavirus vaccine effectiveness data from a developing country. The successful public-private partnership (PPP) was internationally recognized as a model for the rapid adoption of a new vaccine in a developing world setting. The model could be adapted to benefit other PPPs interested in demonstrating the impact of their own programs.

Retrospective analysis of the results of acellular pertussis vaccine toxicity tests performed in Korea

Hokyung Oh, Jeewon Joung, Byoungguk Kim, Halim Lee, Woosun Lee, Seung-Hwa Hong and Byung-Yoon Ahn
Pages 783 - 787
http://dx.doi.org/10.4161/hv.19837
Abstract | Full Text | PDF

Specific toxicity test is a major quality control test for acellular pertussis (aP) vaccines performed by manufacturers and regulatory authorities. The ‘mouse body weight gain test (MWGT)’, the ‘leukocytosis-promoting test (LPT)’ and the ‘histamine sensitization test (HIST)’ have been conducted to check the specific toxicity of all batches of aP vaccines used in Korea through the national quality control program, which requires a lot of animals, labor and time. In this study, test results obtained in the past 9 y from a total of 258 lots of aP vaccines were examined retrospectively to evaluate the three test methods. A pairwise comparison of the test results indicated a good correlation between LPT and HIST, whereas MWGT showed no correlation with either LPT or HIST. Moreover, the reversion to toxicity was higher than the residual toxicity in the majority of lots tested by HIST, which indicated that the histamine-sensitizing toxicity, although rated within a safe range, increased during the vaccine storage. Thus, the vaccine safety test results accumulated in the past might be useful for the improvement of test protocols.

The burden of hospitalizations for head and neck neoplasm in Spain (1997-2008): An epidemiologic study.

Ruth Gil Prieto, Pablo Viguera, Alejandro Álvaro, María San-Martín and Angel Gil de Miguel
Pages 788 - 798
http://dx.doi.org/10.4161/hv.19819
Abstract | PDF

Background: Cancers of the head and neck currently figure as the 6th most important cause of cancer globally. They are strongly associated with tobacco and alcohol consumption, but recent studies showed the presence of HPV in patients with these types of cancer. The incidence of cancers of the head and neck potentially attributable to HPV has increased in the last years. This study aims to provide population-based estimates of the burden of hospitalisation for head & neck neoplasm in Spain that may be useful when cost-effectiveness models are developed to evaluate the impact of HPV vaccination in Spain. Methods: Epidemiological retrospective survey to assess the burden of hospitalisation for head and neck neoplasm in the general population in Spain during the 1997-2008 period. Differences in proportions were assessed by the Chi-square test. ANOVA was used for multiple comparisons. The post hoc Bonferroni correction was used to adjust statistical significance for multiple comparisons. Poisson regression was used to assess differences in the hospitalisation rate during the study period in all the age groups. Results: A total of 199,304 hospital discharges for head and neck malignant neoplasm were recorded during the 12-years of study: 55,475 (46,560 males and 8,915 females) corresponded to oral cavity; 46,699 (45,020 males and 1,679 females) to pharynx and 97,139 (93,374 males and 3,765 females) to larynx malignant neoplasms. Hospitalization rates increased significantly with age. Overall hospitalization rates in men were more than 10-fold higher than in women. Rates decreased significantly in men during the study period but increased significantly in women in all locations. Conclusions: Although a slight decrease has been observed in hospitalization rates due to head and neck neoplasm in the last years in men, they still generate a substantial morbidity and mortality, especially in adults over 50 years of age.

Antibody response to Streptococcus pneumoniae proteins PhtD, LytB, PcpA, PhtE and Ply after nasopharyngeal colonization and acute otitis media in children

Michael E. Pichichero, Ravinder Kaur, Janet R. Casey, Qingfu Xu, Anthony Almudevar and Martina Ochs
Pages 799 - 805
http://dx.doi.org/10.4161/hv.19820
Abstract | Full Text | PDF

We prospectively compared serum antibody levels of 5 Streptococcus pneumoniae (Spn) proteins: PcpA PhtD, PhtE Ply and LytB associated with nasopharyngeal (NP) colonization and acute otitis media (AOM) infection in a cohort of 6–30 mo old children. Antigen-specific antibody titers were determined by ELISA. A total of 731 visits among 168 children were studied. There were 301 Spn NP colonization episodes documented in 109 (65%) children and 42 Spn AOM episodes in 34 (20%) children. IgG antibody titers to the 5 proteins were significantly different among children over time (p < 0.001), with a rank order as follows: PcpA > PhtE = PhtD > Ply > LytB Characterization of IgG and IgM acute and convalescent serum antibody levels of Spn AOM infection showed the kinetics of the response differed among children, with the same rank order of antibody levels over time. Individual data showed that some children responded to AOM with an antibody increase to one or more of these Spn proteins but some children failed to respond. We conclude that antibody levels to Spn proteins PcpA PhtD, PhtE, Ply and LytB, all rise over time in children age 6 to 30 mo following natural exposure to Spn after NP colonization and AOM; however, there were significant differences in quantity of antibody elicited among these potential vaccine antigens.

Immunogenicity, reactogenicity and safety of a human rotavirus vaccine (RIX4414) in Korean infants: A randomized, double-blind, placebo-controlled, phase IV study

Jung Soo Kim and 20 others
Pages 806 - 812
http://dx.doi.org/10.4161/hv.19853
Abstract | PDF

Rotavirus (RV) infection is the primary cause for childhood gastroenteritis worldwide. In Korea, RV infection is most common among children less than 5 y of age. This post-licensure study was conducted to further evaluate the RV vaccine (RIX4414) to provide additional local clinical data to the Korean Food and Drug Association. Healthy infants aged 6–12 weeks were enrolled to receive two doses of either RIX4414 or placebo as per 0, 1–2 mo schedule. Blood samples were collected before dose-1 and one month post-dose-2 of RIX4414/placebo to assess serum anti-RV IgA antibody concentrations using ELISA. Gastroenteritis stool samples were tested for the presence of RV using ELISA. RV positive samples were subjected to further analysis for G and P typing. Among 684 infants enrolled and vaccinated, 432 infants (RIX4414 = 318; placebo = 114) were included in the according-to-protocol cohort for immunogenicity. The anti-RV IgA antibody seroconversion rates in the RIX4414 group following one month post-dose-2 were 88.1% (95% CI: 84.0–91.4) and the corresponding geometric mean concentration in the RIX4414 group was 208.5 U/ml (95% CI: 174.2–249.5). Occurrence of solicited and unsolicited adverse events were similar in both, RIX4414 and placebo groups. None of the gastroenteritis stool samples tested positive for RV and no fatal SAEs were reported in either groups. The two-dose regimen of RIX4414 was observed to be immunogenic with a similar safety profile as compared with the placebo group, when administered to healthy Korean infants.

Long-term anti-HBs antibody persistence and immune memory in children and adolescents who received routine childhood hepatitis B vaccination

Ulrich Behre, Gerhard Bleckmann, Priya Diana Crasta, Maarten Leyssen, Marc Messier, Jeanne Marie Jacquet and Karin Hardt
Pages 813 - 818
http://dx.doi.org/10.4161/hv.19898
Abstract | PDF

Purpose: This paper presents data from two studies that evaluated 5-year and 10-year persistence of antibodies against hepatitis B (HBV) surface antigen (anti-HBs) and immune response to an HBV vaccine challenge in children and adolescents who had received three doses of a HBV vaccine in infancy as part of routine clinical practice [NCT00519649/ NCT00984139]. Results: Anti-HBs antibody concentrations ³ 10mIU/ml persisted in 83.3% (95% confidence interval [CI]: 78.5−87.5) and 78.3% (95% CI: 73.1−83.0) of subjects aged 7−8 years and 12−13 years, respectively 5−10 years after infant vaccination. One month post-challenge dose, 98.2% (95% CI: 95.9−99.4) and 93.7% (95% CI: 90.2−96.2) of subjects in the two age groups, respectively had anti-HBs antibody concentrations ³ 100mIU/ml. Overall, 99.6% (95% CI: 98−100) and 97.2% (95% CI: 94.5−98.8) of subjects aged 7−8 years and 12−13 years mounted an anamnestic response to the HBV challenge dose, which was well-tolerated. Methods: Healthy children aged 7−8 years and adolescents aged 12−13 years received three doses of a monovalent pediatric HBV vaccine (10µg of HBsAg) before 18 months of age. Serum samples collected before and one month post-HBV vaccine challenge dose were tested for anti-HBs antibody concentrations. Safety assessments were made for the HBV vaccine challenge dose. Conclusions: A three-dose childhood HBV immunization regimen induced persistence of antibodies against HBV infection for 10 years, up to adolescence. This vaccination regimen also conferred long-term immune memory against HBV as evidenced by the strong anamnestic response to the HBV vaccine challenge, despite waning anti-HBs antibody levels.




COMMENTARIES

Malaria vaccine: A bright prospect for elimination of malaria

Mohan Bairwa, Meena Rajput, Pardeep Khanna, Ravi Rohilla, Ramesh Verma and Sumit Chawla
Pages 819 - 822
http://dx.doi.org/10.4161/hv.20145
Abstract | Full Text | PDF

Malaria remains one of the few diseases those continue to scourge human civilization despite the significant advances in disease control strategies over the last century. Malaria is responsible for more than 500 million cases and 1–3 million deaths annually. Approximately 85% of these deaths are among children, mostly in Africa, primarily due to P. falciparum. Whole cell vaccines, irradiated sporozoites and genetically attenuated sporozoites have demonstrated long lasting, sterile protection against plasmodium infection in animal and experimental clinical studies. Atypical membrane protein 1 and merozoite surface protein 1 are the two most extensively studied asexual blood stage vaccine candidates. The most promising candidate vaccine under development is RTS, S combined with AS01 adjuvant. Initial results from phase III trials of this candidate vaccine show 50% reduction of malaria in 5–17 mo aged children during the 12 mo after vaccination. WHO anticipates that the RTS,S/AS01 vaccine will be recommended for the 6–14 week age group for co-administration together with other vaccines as part of routine immunization programs in malaria endemic countries. Malaria vaccine could play an important role in elimination and eventual eradication of malaria.

Hepatitis E vaccine development: A 14 year odyssey

Ting Wu, Shao-Wei Li, Jun Zhang, Mun-Hon Ng, Ning-Shao Xia and Qinjian Zhao
Pages 823 - 827
http://dx.doi.org/10.4161/hv.20042
Abstract | Full Text | PDF

The first prophylactic vaccine, Hecolin®, against hepatitis E virus (HEV) infection and the HEV associated disease was approved by China's State Food and Drug Administration (SFDA) in December 2011. Key milestones during the 14-year HEV vaccine development are summarized in this commentary.  After years of innovative research the recombinant virus-like particle (VLP) based antigen with virion-like epitopes was successfully produced in E. coli production platform on a commercial scale. Safety and efficacy of this vaccine was demonstrated in a large scale phase III clinical trial.

Value for money from HPV vaccination and cervical screening

Toni Ashton and Elizaveta Sopina
Pages 828 - 830
http://dx.doi.org/10.4161/hv.19807
Abstract | PDF

Introduction of human papillomavirus (HPV) vaccination programs raises some important questions about the future organization of cervical screening programs. Two studies—from NZ and Canada—have addressed the question of what combination of vaccination and screening strategies might be most cost-effective in preventing cervical cancer. Both studies indicate that some modifications to existing screening programs may be desirable as immunized females enter these programs. Variables in HPV vaccination that are likely to be particularly important for determining the future cost-effectiveness of cervical screening programs include: vaccine uptake rate, compliance with full doses, timely completion of doses, duration of protection, male vaccination and HPV infection rate. If value for money is to be achieved, it is important that the appropriate data are collected so that policy makers can consider the combined impact of these two programs on costs and health outcomes.

Rubella vaccine: New horizon in prevention of congenital rubella syndrome in the India

Ramesh Verma, Pardeep Khanna and Suraj Chawla
Pages 831 - 833
http://dx.doi.org/10.4161/hv.19584
Abstract | Full Text | PDF

Rubella is a contagious viral disease, which mainly affects the fetus, if the mother is infected in the 1st trimester of her pregnancy. All adolescent girls (aged 11 to 19 y) and women of childbearing age are at risk of developing rubella. This disease is mild and self-limiting, and incubation period is 2–3 weeks. Humans are the only hosts for rubella. Rubella infection during pregnancy may lead to abortions, stillbirth or congenital deformities (birth defects). Moreover it is surprising to know that over 200,000 babies are born with birth defects because of Rubella infection during pregnancy in the Indian sub-continent. The risk of fetal infection is highest in first trimester; the infection rate declines between 12–28 weeks, suggesting that the placenta may prevent transfer of virus but not completely. The incidence of defects is inversely related to the time of maternal infection. Rubella outbreaks have been reported from many countries in South East Asian region with congenital rubella syndrome (CRS) due to maternal rubella being on the increase in many countries. In India, although the endemicity of rubella is established, the majority of cases remain undiagnosed, being subclinical or clinically mild. Consequently, in spite of evidence of CRS in all States of India, no distinct policy has been envisaged for assessing the burden of rubella, and no control measures against this silent crippling disease are in place. The European Regional Committee of the World Health Organization has adopted the goals of “Elimination of CRS” in the Health for All programs. There is no treatment for rubella. Vaccination is the only way to prevent all these complications.

Insulin-specific vaccination for type 1 diabetes: a step closer?

Leonard C. Harrison
Pages 834 - 837
http://dx.doi.org/10.4161/hv.19673
Abstract | PDF

Vaccination against self-antigens to avert pathological immunity to self - ‘negative vaccination’ - is the Holy Grail of autoimmune disease therapy. This approach depends on deletion or inactivation of pathogenic T cells, or induction of protective, ‘regulatory’ T cells. While effective in inbred rodent models, it is yet to be translated to humans. Reasons for this include its application only in end-stage disease, ignorance about antigen form, route of delivery and dose-schedule required for a bio-response, lack of meaningful and measurable bio-response markers, co-activation of pathogenic immunity and genetic heterogeneity.

Implications of philosophical and personal belief exemptions on re-emergence of vaccine-preventable disease: The role of spatial clustering in under-vaccination

Kacey Ernst and Elizabeth T. Jacobs
Pages 838 - 841
http://dx.doi.org/10.4161/hv.19743
Abstract | PDF

Vaccine exemption policies vary by state, and it has been demonstrated that easier protocols for personal/ philosophical belief exemptions are associated with lower vaccine coverage at the state level. However, this does not lead to ubiquitously lower immunization rates across the state, as shown by variability in county-level exemption rates. Rather, there is geographical clustering of areas which are then more vulnerable to outbreaks of vaccine-preventable diseases. Understanding both state and local patterns of vaccine exemptions and developing policies and public health interventions to increase coverage in high-risk areas is critical. At all levels of healthcare, efforts must be made to encourage vaccination education and legislation to protect the public’s health.

Mathematical models of the interplay between individual vaccinating decisions and disease dynamics: a need for closer integration of models and data

Samit Bhattacharyya and Chris Bauch
Pages 842 - 844
http://dx.doi.org/10.4161/hv.19616
Abstract | PDF

In non-mandatory vaccination policies, individual choice can be a major driver of vaccine uptake. Choice thereby influences whether public health targets can be achieved. Individual vaccinating decisions can be influenced by perceptions of vaccine risks or infection risks. There is also the potential for non-vaccinators to strategically 'free-ride' on herd immunity provided by vaccinators. This strategic interaction between individuals generates a social dilemma--a conflict between self-interest and what is best for the group as a whole. Game theory and related mathematical approaches that couple mechanistic models of vaccinating decisions with mechanistic models of disease spread can capture this social dilemma and address relevant questions. The past decade has seen significant growth in the theoretical literature developing and analyzing such models. Here, we argue that using these models to address specific public health challenges will require more work that integrates information from empirical studies into the development and validation of such models, as well as more collaboration between mathematical modelers, psychologists, economists and public health experts.