Table of Contents

Volume 8, Issue 5

  May 2012

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REVIEW

Open Access Article

Lessons learned and applied: What the 20th century vaccine experience can teach us about vaccines in the 21st century

Corey Joseph Hebert, Corey Hall and La’ Nyia J. Odoms
Abstract | Full Text | PDF

Most vaccines available in the United States have been incorporated into vaccination schedules for infants and young children, age groups particularly at risk of contracting infectious diseases. High universal vaccination coverage is responsible for substantially reducing or nearly eliminating many of the diseases that once killed thousands of children each year in the US.




RESEARCH PAPERS

Background morbidity in HIV vaccine trial participants from various geographic regions as assessed by unsolicited adverse events

Claudia Schmidt and 30 others
Abstract | Full Text

Background: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers.

 

Objective

To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents.

Methods

All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded.

Results

In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders.

Conclusions

Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.

Safety assessment and immunogenicity of a cell-culture-derived influenza vaccine in adults and elderly subjects over three successive influenza seasons

Agnieszka Szymczakiewicz-Multanowska, Maria Lattanzi, Allen Izu, Daniela Casula, MariaVittoria Sparacio, Csaba Kovacs and Nicola Groth
Abstract | Full Text

Background

Adult and elderly subjects previously immunized with cell culture-derived (CCIV; Optaflu^®) or egg-derived (TIV; Agrippal^®) trivalent influenza vaccines were enrolled in two extension studies (E1 and E2) to evaluate safety and immunogenicity after revaccination with CCIV/TIV alone or in combination with concomitant pneumococcal vaccine (PV).

Methods

Adults and elderly subjects (n = 2609) were randomized 1:1 in E1 and allocated 3:1 in E2 to receive CCIV/TIV. In E2, a subset of elderly subjects was randomized to receive CCIV/TIV, with or without PV. Adverse reactions were monitored for six months and immunogenicity was assessed by hemagglutination inhibition (HI) assay using CHMP criteria.

Results

Overall, the safety profile of both vaccines was similar, no serious adverse events related to either vaccine occurred. Mild or moderate pain was the most commonly reported reaction. Reactogenicity was slightly higher in elderly subjects receiving CCIV/TIV concomitantly with PV (46% vs. 37%; p = non-significant (NS)) .Both vaccines met CHMP licensure criteria for adults and elderly subjects. With concomitant CCIV and PV, all three CHMP criteria were met for A/H1N1 and A/H3N2, whereas the B strain only met seroprotection and GMR criteria.

Conclusions

Safety and immunogenicity of CCIV was not influenced by the type of vaccine received previously or by concomitant PV administration.

Open Access Article

The human potential of a recombinant pandemic influenza vaccine produced in tobacco plants

Asne Jul-Larsen, Abdullah Madhun, Karl Brokstad, Emanuele Montomoli, Vidadi Yusibov and Rebecca Cox
Abstract | Full Text

Rapid production of influenza vaccine antigen is an important challenge when a new pandemic occurs. Production of recombinant antigens in plants is a quick, cost effective and up scalable new strategy for influenza vaccine production. In this study, we have characterized a recombinant influenza haemagglutinin antigen (HAC1) that was derived from the 2009 pandemic H1N1 virus and expressed in tobacco plants. Volunteers vaccinated with the 2009 pH1N1 oil-in-water adjuvanted vaccine provided serum and lymphocyte samples that were used to study the immunogenic properties of the HAC1 antigen in vitro. By 7 d post vaccination, the vaccine fulfilled the licensing criteria for antibody responses to the HA detected by haemagglutination inhibition and single radial hemolysis. By ELISA and ELISPOT analysis we showed that HAC1 was recognized by specific serum antibodies and antibody secreting cells, respectively. We conducted a kinetic analysis and found a peak of serum HAC1 spec antibody response between day 14 and 21 post vaccination by ELISA. We also detected elevated production of IL-2 and IFNγ and low frequencies of CD4+ T cells producing single or multiple Th1 cytokines after stimulating PBMCs (peripheral blood mononuclear cells) with the HAC1 antigen in vitro. This indicates that the antigen can interact with T cells, although confirming an effective adjuvant would be required to improve the T-cell stimulation of plant based vaccines. We conclude that the tobacco derived recombinant HAC1 antigen is a promising vaccine candidate recognized by both B- and T cells.




COMMENTARIES

Increase of meningococcal serogroup Y cases in Europe: A reason for concern?

Michael Bröker, Susanne Jacobsson, Lisa DeTora, David Pace and Muhamed-Kheir Taha
Abstract | PDF

Neisseria meningitidis is differentiated into 12 distinct serogroups of which A, B, C, W-135, X and Y are medically most important and represent a major health problem in one or more parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. A sudden increase or decrease of IMD or meningococcal carriage may occur anywhere at any time. Recent epidemiological surveillance indicates an increase of serogroup Y IMD in some parts of Europe and data from various European countries are presented.

The mucosal vaccine Qquandary: Intranasal vs. sublingual immunization against influenza

Gabriel Pedersen and Rebecca Cox
Abstract | PDF

Intranasal vaccination can effectively induce both local and systemic immune responses and protect against influenza, but poses a risk of antigen or adjuvant delivery into the central nervous system (CNS). Sublingual vaccine delivery has recently received increased attention as a safer alternative to the intranasal route. Studies comparing the two routes have found that higher immune responses may be induced by intranasal than sublingual administration, possibly as a consequence of the differences in mucosal tissues between the two routes. Here we examine evidence of antigen transport into the CNS following intranasal immunisation and discuss possible reasons for the superiority of the intranasal as compared with the sublingual route in terms of vaccine immunogenicity. We encourage generation of more information on the safety of mucosal adjuvants and propose that the next generation of vaccines and adjuvants may be designed specifically for administration via the different mucosal routes.





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RECENTLY ACCEPTED AND COMING SOON

REVIEWS

Vaccination against viral hepatitis of HIV-1 infected patients

Bao-Chau Phung and Odile Launay
Abstract

Reciprocal interactions between HIV and HAV or HBV can increase risk of morbidity and mortality in HIV disease and/or worsened the natural course of the hepatitis viruses. Hepatitis A vaccination is recommended for HIV infected patients at risk for exposure or severe disease: men who have sex with men, injecting drug users, patients with chronic liver disease and patients traveling in high endemic countries. As for healthy adults the scheme of vaccination is two doses 6 or 12 mo apart, nevertheless seroconversion rates are lower. A third dose could improve the seroconversion rates. Hepatitis B vaccination is recommended for all HIV infected persons lacking prior immunity. As the immune response to hepatitis B vaccines is impaired in HIV-infected adults, four double doses of hepatitis B vaccine could enhance serological response. To assume a higher immune response, vaccines should be administered in HIV-infected patients with undetectable HIV viral load and high CD4 cell count.

Therapeutic vaccines against HIV infection

Felipe García, Agathe León, Josep M. Gatell, Montserrat Plana and Teresa Gallart
Abstract

Resistance to medication, adverse effects in the medium-to-long-term and cost all place important limitations on lifelong adherence to combined antiretroviral therapy (cART). In this context, new therapeutic alternatives to ‘cART for life’ in HIV-infected patients merit investigation. Some data suggest that strong T cell-mediated immunity to HIV can indeed limit virus replication and protect against CD4 depletion and disease progression. The combination of cART with immune therapy to restore and/or boost immune-specific responses to HIV has been proposed, the ultimate aim being to achieve a ‘functional cure’. In this scenario, new, induced, HIV-specific immune responses would be able to control viral replication to undetectable levels, mimicking the situation of the minority of patients who control viral replication without treatment and do not progress to AIDS. Classical approaches such as whole inactivated virus or recombinant protein initially proved useful as therapeutic vaccines. Overall, however, the ability of these early vaccines to increase HIV-specific responses was very limited and study results were discouraging, as no consistent immunogenicity was demonstrated and there was no clear impact on viral load. Recent years have seen the development of new approaches based on more innovative vectors such as DNA, recombinant virus or dendritic cells. Most clinical trials of these new vectors have demonstrated their ability to induce HIV-specific immune responses, although they show very limited efficacy in terms of controlling viral replication. However, some preliminary results suggest that dendritic cell-based vaccines are the most promising candidates. To improve the effectiveness of these vaccines, a better understanding of the mechanisms of protection, virological control and immune deterioration is required; without this knowledge, an efficacious therapeutic vaccine will remain elusive.




CASE REPORT

Meningococcal polysaccharide vaccine failure in a patient with C7 deficiency and a decreased anti-capsular antibody response

Paul B. Keiser and Michael Broderick
Abstract

A 20-y-old male presented with symptoms of meningococcal sepsis and died despite appropriate medical interventions. Blood cultures grew N. meningitidis serogroup Y. The patient had received the meningococcal quadrivalent (A,C,W-135,Y) polysaccharide vaccine 15 mo previously. Because the patient had a history of meningococcal meningitis at age 10, archived serum was obtained for further analysis. Complement component C7 was found to be deficient, and antibody levels to meningococcal polysaccharides were undetectable for two serogroups and low for the infecting serogroup 10 mo post-vaccination. This case highlights the fact that some individuals with terminal complement component deficiencies mount an impaired or short-lived response to vaccination with meningococcal capsular polysaccharides, and underscores the appropriateness of a more aggressive vaccination strategy in this patient population.




SHORT REPORTS

Low response to a monovalent inactivated unadjuvanted influenza A (H1N1) pdm09 vaccine in pediatricians of a general hospital in Japan

Atsuko Hata, Chihiro Mano, Yoshie Nakamura, Hitoshi Nishida, Akira Kumakura, Hiroshi Mizumoto, Takakazu Yoshioka, Yoko Yoshida, Mitsutaka Shiota, Daisuke Hata and Kazuo Takahashi
Abstract

Immunization of health care personnel (HCP) is critically important to reduce healthcare-associated influenza infections substantially. During 2009–2010, 74% of all HCP at Kitano Hospital, Osaka, Japan, including 94% of pediatricians, received the monovalent unadjuvanted influenza A (H1N1) pdm09 vaccine.

 

We evaluated the vaccine’s immunogenicity. Sixteen pediatricians received 15 μg hemagglutinin antigen subcutaneously. Antibody titer assays were conducted using hemagglutination-inhibition antibody assay on days 0 and 21, and at 5 mo after vaccination. Seroprotection rates, seroconversion rates, and geometric mean titer folds at 21 d were, respectively, 43.8%, 43.8%, and 5.4 in all subjects, 70.0%, 70.0%, and 8.0 in subjects aged 27–34 y, and 0.0%, 0.0%, and 8.0 in subjects aged ≥ 35 y. None of the latter group met the European Medicines Agency criteria.

We hope to adopt intradermal routes and further the development of the influenza vaccine using new technology to improve immunogenicity in Japan.

Incidence of adverse events in premature children following 2-mo vaccination

Kumanan Wilson and Steven Hawken
Abstract

Using a population based self-controlled case series study design we examined data on 834 740 children in the province of Ontario, Canada. We observed that when comparing to SGA10 term children (term children born in the lowest 10th percentile of weight for a given gestational age), relative incidence of emergency room visits and admission in the 3 d post 2 mo vaccination progressively decreased in near term (relative incidence ratio 0.89 (95% CI 0.74–1.07)) and very premature children (0.67(0.49–0.93). When compared with all term children this decrease in risk is not statistically significant. We speculate that the immune response is reduced in premature children resulting in reduced adverse events. This is masked when comparing to all term children because the reduced birth weight of premature children results in a comparatively increased dose of vaccine. This in turn results in an increased immune response and risk of immediate adverse reactions. Future studies of immune response in premature children should examine the impact of weight at the time of immunization.




RESEARCH PAPERS

Social support of low-income Brazilian mothers related to time to completion of childhood vaccinations

Pamela Surkan, Samara Kiihl, Naoko Kozuki and Lina M. Carvalho Vieira
Abstract

Our study objective was to examine how maternal social support and depressive symptoms are associated with time to completion of childhood vaccinations. We used cross-sectional data from 582 randomly-selected, low-income Brazilian children. Adjusted Cox Proportional Hazard models were used to estimate time to completing the first three recommended oral polio and diphtheria, pertussis and tetanus (DPT) vaccinations as well as their booster doses. Among only the women with low social support, each ten-point increase on the Medical Outcomes Study – Social Support Scale was associated with a 20% increased chance of completing the first three recommended vaccinations for polio and DPT at any given time (HR = 1.20, 95% CI 1.02–1.42). Although falling short of statistical significance, also among mothers with low social support, we found a suggestive finding of increased social support associated with 25% greater chance of completing polio and DPT booster vaccines at any given time (HR = 1.25, 95% CI 0.98–1.60). There was no association between maternal depressive symptoms and vaccination completion. Among mothers with little social support, increased social support may be important for timely completion of vaccinations in low-income Brazilian children. Longitudinal studies and research on mechanisms explaining associations between maternal social support and childhood vaccination are needed.

Titering of 2009 pandemic H1N1 influenza virus hemagglutinin inhibition antibody in nonvaccinated pregnant women in Shiraz, Southern Iran

Behnam Honarvar, Mohsen Moghadami, Afagh Moattari, Amir Emami, Hamid Reza Tabatabaee, Bahia Namavar Jahromi, Nassrin Assadi, Ali Mousavizadeh, Kamran Bagheri Lankarani, Hasan Joulaei and Fariborz Ghaffarpasand
Abstract

Influenza may cause severe complications for pregnant women. In this study antibody response against 2009 H1N1 influenza virus in pregnant women was investigated. This seroprevalance cross sectional and questionnaire based study was conducted using a convenient sampling method. Blood samples of pregnant women were checked for antibodies against 2009 H1N1 influenza virus using hemagglutination inhibition assay. An antibody titer level of ≥ 1:40 dilution was considered as the protective level. 167 (43.60%) of 383 pregnant women who participated in this study had protective antibody levels against this virus. 62 (35.63%) of 3rd trimester, 79 (46.74%) of 2nd trimester, and 21(52.50%) of 1st trimester pregnant women were immune respectively (χ2_{for trend} = 8.20, p < 0.004). Lack of protective antibody level was significantly seen more in pregnant women of 3rd trimester of pregnancy (OR = 2.37, CI = 1.09–5.18). Pregnant women with higher education (OR = 1.67, CI = 1.02–2.73) and those with history of anemia (OR = 2.09, CI = 1.18–3.68) had more immunity. Older women (OR = 0.95, CI = 0.91–0.99) and those with history of psychological diseases (OR = 0.19, CI = 0.05–0.70) had less immunity. Vaccination of pregnant women, especially those who are in the higher trimesters of pregnancy, older, or less educated, against the 2009 H1N1 influenza virus should be continued.

Immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal non-typeable Hemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with the DTPw-HBV/Hib vaccine in Indian infants: a single-blind, randomized, controlled study

Sanjay Lalwani, Sukanta Chatterjee, Jugesh Chhatwal, Valsan P. Verghese, Shailesh Mehta, Fakrudeen Shafi, Dorota Borys, Marta Moreira and Lode Schuerman
Abstract

In India, pneumococcal diseases are major causes of child mortality, and effective vaccines against Streptococcus pneumoniae are needed. This single-blind, randomized study assessed the immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Hemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) co-administered with DTPw-HBV/Hib in Indian infants as 3-dose primary vaccination course. A total of 360 infants were randomized (2:1) to receive either PHiD-CV co-administered with DTPw-HBV/Hib (PHiD-CV group) or a Hib vaccine co-administered with DTPw-HBV (control group) at 6, 10, and 14 weeks of age. For each vaccine pneumococcal serotype, the percentage of infants in the PHiD-CV group with antibody concentrations ≥ 0.2 µg/mL one month after the third vaccine dose was at least 98.3%, except for serotypes 6B (77.7%) and 23F (89.5%), and opsonophagocytic activity titers ≥ 8 were measured in at least 95.7% of infants, except for serotypes 1 (90.5%) and 6B (84.5%). In addition, all the infants in the PHiD-CV group were seroprotected against diphtheria, tetanus, Hib, and hepatitis B or seropositive for antibodies against pertussis and NTHi protein D (except one infant). Incidences of solicited local and general symptoms were comparable between groups, except for fever (axillary temperature ≥ 37.5°C), which seemed to occur more frequently in the PHiD-CV group. In conclusion, PHiD-CV was shown to be immunogenic and well-tolerated when co-administered with DTPw-HBV/Hib in Indian infants.

A randomized trial of immunotherapy for persistent genital warts

David Jardine, Jieqiang Lu, James Pang, Cheryn Palmer, Quanmei Tu, John Chuah and Ian H. Frazer
Abstract

Aim: To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy.

 

Trial Design: A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China.

Methods: Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1µg, 5µg or 25µg of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts.

Results: Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% +/− s.e.m. 7%) recipients for subjects receiving 5µg or 25µg of VLP immunotherapy/dose (71% +/− s.e.m.7%) but not for those receiving 1µg VLP immunotherapy/dose (42% +/−7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 ± 1.1 mths) than in Brisbane subjects (53.7 ± 5.5 mths). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy.

Conclusions: This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing prior disease duration.

Clinical effectiveness of 23-valent pneumococcal polysaccharide vaccine against pneumonia in patients with chronic pulmonary diseases: A matched case-control study

Angel Vila-Corcoles, Olga Ochoa-Gondar, Teresa Rodriguez-Blanco, Antonia Gutierrez-Perez, Angel Vila-Rovira and EPIVAC Study Group
Abstract

Background

The effectiveness of the 23-valent polysaccharide pneumococcal vaccine (PPV-23) is controversial, especially among people with high-risk conditions. This study assessed the clinical effectiveness of vaccination against pneumonia among patients with chronic pulmonary diseases.

Methods

We conducted a population-based case-control study including 96 non-immunocompromised patients with clinical diagnosis of chronic pulmonary disease (chronic bronchitis, emphysema and/or asthma), aged 50 y or older, with radiographically confirmed pneumococcal pneumonia (19 bacteremic and 77 nonbacteremic cases) and 192 outpatient control subjects with similar chronic pulmonary diseases (matched by primary care center, age, sex and main comorbidity). Adjusted odds ratios (ORs) for vaccination were calculated using conditional logistic regression, controlling for by underlying conditions.

Results

Pneumococcal vaccination did not alter significantly the risk of overall pneumococcal pneumonia [adjusted OR: 0.71; 95% confidence interval (CI): 0.37–1.39]. Point estimates of vaccine effectiveness was the maximum against bacteremic pneumococcal pneumonia due to vaccine-serotypes, although neither reached statistical significance (adjusted OR: 0.51; 95% CI: 0.03–8.19). Vaccination pointed to a smaller benefit against nonbacteremic pneumococcal pneumonia (adjusted OR: 0.66; 95% CI: 0.33–1.34). Pneumococcal vaccination was associated with a non-statistically significant reduction in the risk of all pneumococcal pneumonia among persons 75 y or older (adjusted OR: 0.45; 95% CI: 0.16–1.27), but no apparent protective effect emerged among people 50–74 y (adjusted OR: 1.48; 95% CI: 0.62–3.56).

Conclusions

The effectiveness of the PPV-23 in preventing pneumonia among patients with chronic pulmonary disease is uncertain. Our results point to PPV-23 having little or null effect against pneumococcal pneumonia in such patients, but definitive conclusions cannot be established based on our data.

Parental views on vaccine safety and future vaccinations of children who experienced an adverse event following routine or seasonal influenza vaccination in 2010

Adriana Parrella, Mike Gold, Helen Marshall, Annette Braunack-Mayer, Maureen Watson and Peter Baghurst
Abstract

To assess parental vaccine safety views and future vaccination decisions after an adverse event following immunisation (AEFI) experienced by their child. A cross-sectional telephone survey was conducted of parents of children aged 0–7 y, identified in AEFI reports submitted to the South Australian Immunisation Section, Department Health. The reports included childhood National Immunisation Program (NIP), seasonal or pandemic influenza vaccines. Interviews were conducted following a national suspension of the 2010 seasonal trivalent influenza (STIV) vaccine. Parental attitudes toward vaccine safety, reasons for reporting the AEFI and impact on future vaccination intent were assessed. Of 179 parents interviewed, 88% were confident in the safety of vaccines in general. Parents reporting an AEFI to the STIV were more likely to state the event had influenced future vaccination decisions than the NIP vaccine reporters (65% vs 14%, p < 0.001), with 63% stating refusal or hesitance to re-vaccinate their children against influenza. Media reports of the 2010 STIV program suspension was the most common reason for reporting an AEFI for parents of children who received an influenza vaccination. The AEFI experience did not impact on parental decision to continue with routine childhood NIP schedules, regardless of whether children received influenza or NIP vaccines. In contrast, most parents whose child experienced an AEFI to the 2010 STIV stated decreased confidence in the safety of influenza vaccines, which is likely to have impacted on the uptake of seasonal influenza vaccination in 2011. Addressing influenza vaccine safety concerns to promote influenza vaccination in the community is required.

Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: An open label, phase 1 clinical trial

Fan-Yue Meng, Jing-Xin Li, Xiu-Ling Li, Kai Chu, Yun-Tao Zhang, Hong Ji, Liang Li, Zheng-Lun Liang and Feng-Cai Zhu
Abstract

In this open labeled phase 1 clinical trial with enterovirus 71 (EV71) vaccine (ClinicalTrials.gov number: NCT01267903) performed in Donghai County, Jiangsu Province, China, in January 2011. A total of 100 healthy participants, stratified by age (40 adults aged 16–22 y and 60 children aged 6–15 y), were enrolled from volunteers and sequentially received EV71 vaccines of 160U (only for children), 320U, or 640U on day 0 and 28, in a manner of dose escalation. All the participants were followed for 28 d after each shot. During the study period, 37 participants reported at least one injection-site or systemic adverse reaction. No case of grade 3 adverse reaction or serious adverse event (SAE) was observed. Also no dose-related increase in reaction rate was noticed. Pain at injection-site and fever were the most frequently reported local and systematic reaction, respectively. The studied EV71 vaccines demonstrated acceptable tolerability and no anti-nuclear antibody (ANA) seropositive was detected pre or post vaccinations in participants. Also, no clinically significant abnormal change for the liver or kidney function indexes was found. In the according-to-protocol cohort for immunogenicity, it was observed one dose of EV71 vaccine elicited good immune response in the participants, especially for the ones with sero-positive baseline. No obvious dose-response relationship for immunogenicity was found. This study was co-founded by Beijing Vigoo Biological Co., LTD and Chinese governmental grants (2008BAI69B01 and 2009ZX10004–806).




COMMENTARIES

Influenza Vaccine: An effective preventive vaccine for developing countries

Ramesh Verma, Pardeep Khanna and Suraj Chawla
Abstract

The Influenza virus A, B and C causes disease in humans, birds and animals. The Influenza type A causes moderate to severe illness in all age groups in humans while the illness caused by type B is of milder and it is primarily affects children. Among many subtypes of influenza A viruses, currently influenza A(H1N1) and A(H3N2) subtypes are circulating among humans. Influenza is a serious public health problem that causes severe illnesses and deaths for higher risk populations. Influenza virus is characterized by frequent mutations – antigenic drifts (minor antigenic change, both A and B) and antigenic shifts (major antigenic change, only A). The current human pandemic A/H1N1 is an example of antigenic shift. It slowly established circulation globally; subsequently endemic/seasonal viruses in both hemi-spheres are H3N2 and H1N1. The novel Influenza A (H1N1) 2009 virus was first identified by United State Centers for Disease Control and Prevention (US CDC) on 17th April, 2009 in samples from two Californian children. As of August 2010, 18,000 people had died globally due to the pandemic flu. The illness rates were highest in children and young adults (20–40% of the population), the hospitalization rates highest in children below the age of one. The case fatality rates varied tremendously and were estimated to be between 0.0004- 1.5% (0.05% in US, 0.025% in UK, lowest in children). The most effective way to prevent the disease or severe outcomes from the illness is vaccination. The Trivalent Inactivated vaccines (TIV) are of three types: whole virus, split-product, subunit surface-antigen formulations and they are grown in embryonated hen's eggs. Whole-virus vaccines, because of adverse reactions, especially in children, are not currently used. Most influenza vaccines are split-product vaccines, produced from detergent treated, highly purified influenza virus, or surface-antigen vaccines containing purified hemagglutinin and neuraminidase.

Designing around patents with an immunotherapy case: A take-home message of a full court decision by the US Federal Circuit

Shyh-Jen Wang
Abstract

In TiVo Inc. V. EchoStar Corp case (2010), all judges of the US Court of Appeals for the Federal Circuit (CAFC) reemphasized that legitimate design around a competitor’s patents is always encouraged as a route of innovation. The modified elements of the design-around must be evaluated against the asserted claim(s) to ensure that each limitation is met before concluding that the modification is not substantially different from the previously adjudged infringed product. Regarding the significance of the differences between the features adjudged as infringement and the modified characteristics of the newly designed products, CAFC stated that the determination may refer to the rule of obviousness.

 

In this article, we present an immunotherapy case that shows how to overcome an obviousness rejection by showing an unexpected result. The new design using an anti-VEGF antibody-encoding sequence in vaccinia virus should significantly increase its therapeutic effect. Furthermore, the newly-designed virus would provide tumor-localized delivery of the antibody and enhance anti-tumor activity.

Cholera vaccine: New preventive tool for endemic countries

Ramesh Verma, Pardeep Khanna and Suraj Chawla
Abstract

Cholera is a major global public health problem and remains an important threat in almost every developing country, especially in areas where population overcrowding and poor sanitation are common, such as slums and refugee camps. Cholera is one of the most dreaded diseases in the world, in some cases leading to death within 24 h if left untreated. Without treatment, severe infection has a mortality rate of 30–50%. In 2007, WHO recorded 177,963 cholera cases and 4,031 deaths worldwide. However, the estimated actual burden of cholera is in the vicinity of 3 to 5 million cases and 100 000 to 130 000 deaths per year. The disease is endemic to parts of Africa, Asia, the Middle East and South America.¹ Large outbreaks are common after natural disasters or in populations displaced by war, where there is inadequate sewage disposal and contaminated water. In India, during the 10-y period (1997–2006) studied, the states having the highest number of reported outbreaks were West Bengal, Orissa, Maharashtra and Kerala, which together accounted for 60% of all reported outbreaks. A review of cholera cases in India reported to WHO from 2003–2007 showed that the numbers were in the few thousands with a case fatality rate of < 1%. However, it is believed that the number of cholera cases and deaths occurring annually in India is much greater than the number reported. A literature review covering a four-year period from 2003 to 2006 found reported cholera outbreaks in 18 of the 35 States and Union Territories of India. Of these, 11 had cholera outbreaks reported for multiple years. Vietnam has produced a cheaper variant of killed whole-cell vaccine devoid of the B subunit. This vaccine contains both Vibrio cholerae O1 and O139, and provides 50 per cent protection for at least three years after vaccination. For endemic cholera, population-level immunity is relatively high, making control possible with relatively low vaccine coverage levels. This vaccine should be used in areas where cholera is endemic, particularly in those at risk of outbreaks, in conjunction with other prevention and control strategies.