Table of Contents

Volume 8, Issue 9

  September 2012

  Pages 1167 - 1363

Special Focus: Cancer Commentary Series

Guest Editors: Michael G. Hanna and Alex Kudrin

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald Ellis and Eva M. Riedmann
Page 1167
http://dx.doi.org/10.4161/hv.22148
Full Text | PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 1168 - 1171
http://dx.doi.org/10.4161/hv.22149
Abstract | Full Text | PDF

Proof of efficacy shown for Sanofi Pasteur’s dengue vaccine
Multi-peptide therapeutic Renal Cell Carcinoma vaccine shows clinical benefit
Poor sleep can reduce effectiveness of vaccines 
Innovative grass pollen allergy vaccine positive in phase 2
GSK’s shingles vaccine starts phase 3 in immunocompromised patients
Overweight? There may be vaccine for that
Vaccination records available online
US females often do not complete HPV vaccination regimens 

Open Access Article

Of [hamsters] and men: A new perspective on host cell proteins

Andres H. Gutiérrez, Leonard Moise and Annie S. De Groot
Pages 1172 - 1174
http://dx.doi.org/10.4161/hv.22378
Abstract | PDF

Over many years, recombinant protein biologics developers have addressed product immunogenicity with a focus on the active pharmaceutical ingredient. Recently, immune responses to the native host cell proteins (HCP) have gained attention, as they too may have an effect on the immune response to the formulated drug, namely diminished drug safety and efficacy. The recent suspension of two clinical trials due to the presence of antibodies to Chinese Hamster Ovary (CHO) HCPs in subjects treated with a recombinant biologic clearly reveals the serious concern regulatory agencies attribute to contaminating HCPs. It appears that even minor amounts of CHO-derived HCP in the final formulation of therapeutics can potentially stimulate an immune response to these contaminants; of even greater concern are immune responses that may be cross-reactive with human proteins. Publication of the CHO-K1 genome and transcriptome provides an opportunity to gain insight into one of the most commonly used expression systems in recombinant protein production. We recently applied immunoinformatics tools to evaluate the immunogenic potential of CHO HCP. Rather than evaluate HCP for their intrinsic potential immunogenicity, we suggest that we should estimate their immunogenicity on a fine-tuned scale that accounts for regions that are homologous to human sequences. As more information on the exact identity of the HCP that drive immunogenicity emerges, the accuracy of this approach is likely to improve.

Bio-process engineers are scrambling to identify means for reducing host cell protein (HCP) content and ways to identify HCP that have the potential to raise antibody responses following the cancellation of two phase III clinical trials. The trials were evaluating the safety and efficacy of Inspiration’s IB1001, a recombinant factor IX produced in CHO cells; the development of anti-Chinese hamster ovary (CHO) antibodies at higher levels than expected in patients treated with IB1001 triggered the FDA ruling.¹ Anti-CHO antibodies did not reduce F.IX efficacy, thus the ruling was presumably not related to drug efficacy, but rather to drug safety.




PORTRAIT

Open Access Article

Portrait of a leader in immunotherapeutics: A passion for biotechnology

William R. Strohl
Pages 1175 - 1178
http://dx.doi.org/10.4161/hv.22150
Abstract | Full Text | PDF

I recently said to Lila, my wife of 25 years, that I had just realized that “science defined my life”. She responded by telling me that she knew that 25 years ago… The story, though, is that it might not have been, and the journey to get to where I am today was a highly circuitous one, taking me places I never thought I would see. Nevertheless, today I can look back on a career as a scientist that has been both fascinating and fulfilling, and…, perhaps the only life I could have lived in complete happiness. My only hope is that, before my career is over, I can give back as much or more than I have received from science.




REVIEWS

Immunotherapy in ovarian cancer

Gina M. Mantia-Smaldone, Bradley Corr and Christina S. Chu
Pages 1179 - 1191
http://dx.doi.org/10.4161/hv.20738
Abstract | PDF

Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012.¹ While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years.^1,2 Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer.^3,4 By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer.

Poxvirus vectors as HIV/AIDS vaccines in humans

Carmen Elena Gómez, Beatriz Perdiguero, Juan García-Arriaza and Mariano Esteban
Pages 1192 - 1207
http://dx.doi.org/10.4161/hv.20778
Abstract | PDF

The RV144 phase III clinical trial with the combination of the poxvirus vector ALVAC and the HIV gp120 protein has taught us that a vaccine against HIV/AIDS is possible but further improvements are still needed. Although the HIV protective effect of RV144 was modest (31.2%), these encouraging results reinforce the use of poxvirus vectors as HIV/AIDS vaccine candidates. In this review we focus on the prophylactic clinical studies thus far performed with the more widely studied poxvirus vectors, ALVAC, MVA, NYVAC and fowlpox expressing HIV antigens. We describe the characteristics of each vector administered either alone or in combination with other vectors, with emphasis on the immune parameters evaluated in healthy volunteers, percentage of responders and triggering of humoral and T cell responses. Some of these immunogens induced broad, polyfunctional and long-lasting CD4⁺ and CD8⁺ T cell responses to HIV-1 antigens in most volunteers, with preference for effector memory T cells, and neutralizing antibodies, immune parameters that might be relevant in protection. Finally, we consider improvements in immunogenicity of the poxvirus vectors by the selective deletion of viral immunomodulatory genes and insertion of host range genes in the poxvirus genome. Overall, the poxvirus vectors have proven to be excellent HIV/AIDS vaccine candidates, with distinct behavior among them, and the future implementation will be dictated by their optimized immune profile in clinical trials.




SHORT REPORTS

Adaptation of a previously validated vaccination report card for use in adult vaccine clinical trials to align with the 2007 FDA Toxicity Grading Scale Guidance

Josephine M. Norquist, Shazia S. Khawaja, Cizely Kurian, T. Christopher Mast, Kai-Li Liaw, Michael N. Robertson, Barbara Evans, David Gutsch and Patricia Saddier
Pages 1208 - 1212
http://dx.doi.org/10.4161/hv.21408
Abstract | Full Text | PDF

The Adult/Adolescent Vaccination Report Card (VRC) was developed and validated by Merck in 1998 for use in vaccine clinical trials to collect information from trial subjects on complaints for both local and systemic events after vaccination. This short report describes the revision to the original validated VRC in order to align with the guidelines outlined in the 2007 FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Since the VRC elicits trial subjects' self-reports of any adverse experiences (AE) occurring post vaccination, it was important that subsequent modifications of the VRC retained the original user-friendly characteristics while gathering the appropriate information to align with the FDA Guidance. A convenience sample of 15 participants (71% females, 87% white and mean (SD) age 45 (13) years was recruited to obtain feedback in order to revise the Adult/Adolescent VRC. Based on the feedback received, the following were slightly revised: ruler for the measurements of local systemic reactions, severity ratings, and general instructions. The revised VRC is currently being used in Merck vaccine clinical trials.

Varicella vaccine uptake in Shandong province, China

Aiqiang Xu, Qing Xu, Xueqiang Fang, Stephanie Bialek and Chengbin Wang
Pages 1213 - 1217
http://dx.doi.org/10.4161/hv.20722
Abstract | Full Text | PDF

Varicella vaccine has been licensed in China for decade to be used as single dose in children aged ≥ 12 mo of age in private sector. Little data were available on varicella uptake to date in China yet. A cross-sectional study was conducted in Shandong Province in May 2011 to examine varicella vaccination coverage among children aged 16–40 mo and examine factors associated with varicella vaccine uptake. The overall coverage among children eligible for varicella vaccine was 62% (range 16.7–94.7% by county), much lower than the coverage of the eight vaccines included in the national immunization program (all above 97%). Though proximity to immunization services (< 5 km) was linked with higher vaccine uptake (62.6 vs. 37.4%, p = 0.02), county-level economic development (77.8, 61.0 and 47.1% for developed, sub-developed and developing regions, respectively, p < 0.001) played an even more important role in varicella vaccination. Moreover, there was little variation in coverage of vaccines included in the national immunization program along with county-level economic development. Even though varicella vaccine uptake is relatively high for use on a private basis, the vaccination coverage is not high enough to prevent epidemiology shift to adolescents and adults who are more prone to develop severe outcomes to varicella. Further enhancement on varicella vaccination coverage is necessary and inclusion to national immunization program seems to be a promising option for achieving and maintaining high coverage.

Comparison of complement dependent lytic, hemagglutination inhibition and microneutralization antibody responses in influenza vaccinated individuals

Mary Dawn T. Co, John Cruz, Akira Takeda, Francis A. Ennis and Masanori Terajima
Pages 1218 - 1222
http://dx.doi.org/10.4161/hv.21025
Abstract | Full Text | PDF

Virus specific, non-neutralizing antibodies such as complement dependent lytic (CDL) antibodies may reduce morbidity following infection through the clearance of infectious virus particles and infected cells. We examined hemagglutination inhibition (HAI), microneutralization (MN) and CDL antibody titers to influenza A H1 and H3 virus strains in 23 healthy young adults who received the 2005–2006 trivalent inactivated influenza vaccine. Post vaccination, we detected statistically significant increases in MN and CDL antibodies but not in HAI antibodies. Statistically significantly higher fold increases in CDL antibodies post vaccination were seen compared with MN and HAI antibodies post vaccination. However, the overall fold increases were modest, likely related to the fact that most of the subjects had received influenza vaccination previously. This study showed that influenza vaccination is not only capable of increasing the level of antibodies that neutralize virus but also antibodies that can cause lysis of infected cells. The biological significance of these CDL antibodies merits further investigation in clinical studies.




RESEARCH PAPERS

Social and cultural determinants of oral cholera vaccine uptake in Zanzibar

Christian Schaetti, Said M. Ali, Raymond Hutubessy, Ahmed M. Khatib, Claire-Lise Chaignat and Mitchell G. Weiss
Pages 1223 - 1229
http://dx.doi.org/10.4161/hv.20901
Abstract | Full Text | PDF

Effectiveness of mass cholera vaccination campaigns requires not only technical and financial capacity but also consideration of social and cultural factors affecting vaccine acceptance. This study examined the influence of local community views of cholera on oral cholera vaccine (OCV) uptake in a mass vaccination campaign in 2009 in peri-urban and rural areas of Zanzibar. It used data from interviews conducted before the campaign and followed previous research assessing determinants of anticipated OCV acceptance. OCV uptake was lower than the reported anticipated acceptance. Less than half of the 356 adult respondents (49.7%) drank the required two doses of OCV. Variables referring to socio-cultural features of diarrheal illness that respondents identified with a cholera case vignette explained uptake better than analysis only of socio-demographic characteristics. Somatic features of illness not specific for cholera were negative determinants. Recognition of unconsciousness as a serious sign of dehydration and concern that cholera outbreaks would overwhelm the local healthcare system in the rural area were positive determinants of acceptance. Female gender, rural residence and older age were also positive determinants of OCV uptake. For further vaccine action with OCVs, cholera as a cause of severe dehydration should be distinguished from other causes of diarrhea. Planning should acknowledge rural concern about the relationship of limited capacity of the healthcare system to cope with cholera outbreaks and the priority of a cholera vaccine. Findings recommend particular efforts to increase cholera immunization coverage among young adults, in peri-urban areas and for men.

Production and evaluation of a chromatographically purified Vero cell rabies vaccine (PVRV) in China using microcarrier technology

Pengcheng Yu, Ying Huang, Yibin Zhang, Qing Tang and Guodong Liang
Pages 1230 - 1235
http://dx.doi.org/10.4161/hv.20985
Abstract | Full Text | PDF

China is a high population country with millions of animal bite cases every year; thus, it is necessary to explore and develop more effective and productive rabies vaccines for human use. To establish a safe, effective, inexpensive and high-yield rabies vaccine, a non-adjuvant purified Vero cell rabies vaccine produced in the SPEEDA PVRV microcarrier bioreactor was developed by Liaoning Chengda Biology Co. Ltd. in China. This vaccine was produced using Vero cells that were cultured in a microcarrier bioreactor. A microcarrier bioreactor containing 25 g/L of Cytodex-1 was used for perfusion culture. The Vero cell culture density was up to 1.2–1.5 × 10⁷ cells/ml, viruses could be constantly harvested for 18–22 days, and the resulting vaccine immunizing potency was ≥ 4.5 IU/ml. Vaccine safety and immunogenicity post-immunization were also assessed. A total of 602 volunteers were enrolled and divided into two groups that were vaccinated with either SPEEDA PVRV or VERORAB PVRV on days 0, 3, 7, 14 and 28. All subjects vaccinated with SPEEDA PVRV showed no serious local or systemic adverse effects. The positive conversion rate of serum neutralizing antibodies against the rabies virus reached 100% in both the test and control groups (inoculated with VERORAB PVRV) at 14 days and 45 days after vaccination, and no significant difference was found between the neutralizing antibody geometric mean titers (GMTs) of the two groups. SPEEDA PVRV is appropriate for mass production and shows satisfactory clinical safety and immunogenicity for human post-exposure prophylaxis of rabies.

Methionine enkephalin (MENK) improved the functions of bone marrow-derived dendritic cells (BMDCs) loaded with antigen

Weiwei Li, Jingjuan Meng, Xuan Li, Hui Hua, Yiming Meng, Qiushi Wang, Enhua Wang and Fengping Shan
Pages 1236 - 1242
http://dx.doi.org/10.4161/hv.21128
Abstract | Full Text | PDF

The aim of this investigation is to look at whether MENK could improve antitumor effect of CD8+T cell elicited by BMDCs. We investigated the effects of MENK on the differentiation, maturation, and functions of murine BMDC loaded with Rac-1 antigens (RG) and CTL of tumor speci□c immune response elicited by the BMDC in vitro and in vivo. The production of cytokine IL-12 and TNF-αsecreted by BMDCs in the presence of MENK was assayed with ELISA and key surface markers of CD40,CD86, CD83 and MHC-II on the BMDCs were analyzed with use of flow cytometry (FCM). In addition, the activities to induce CD8+ T cell proliferation, along with displayed cytotoxicity of the CD8+T cells(CTL) by the BMDCs after treatment with MENK were determined with use of FCM as well as MTS. Our results indicated that MENK induced phenotypic and functional maturation of BMDC loaded with RG antigen, as evidenced by higher level of expression of key surface markers and more production of cytokines. Subsequently, the BMDC activated by MENK intensified immune responses mounted by CTL, resulting in stronger antitumor activity. Our results suggest that MENK could be working as an effective immune adjuvant in vaccine preparation for cancer fight and other immune related diseases. We concluded that MENK could be a positive immune modulator in the improved functions of BMDCs loaded with antigen as well as in CD8+T cell mediated anti-tumor responses.

The regulatory T cells in anti-influenza antibody response post influenza vaccination

Shih-Min Wang, Ming-Hsun Tsai, Huan-Yao Lei, Jen-Ren Wang and Ching-Chuan Liu
Pages 1243 - 1249
http://dx.doi.org/10.4161/hv.21117
Abstract | Full Text | PDF

The efficacy and effectiveness of influenza vaccines depend primarily on the vaccine recipient and the virus similarity to the endemic virus. Regulatory T cells (Tregs) and cytokines are known to restrict immune responses against viral infections. We conducted this study to explore the role of Tregs, cytokines, and antibody production after influenza vaccination. The whole blood was collected from healthy subjects (n = 36) before and two weeks after influenza vaccine immunization for two or three consecutive years. The cell surface markers, intracellular staining of Foxp3⁺ Tregs, and Th1/Th2 cytokines were determined. The antibody titer was detected using the hemagglutination inhibition test. The CD3⁺, CD127⁺, CD4⁺CD25⁺ and CD4⁺Foxp3⁺cells were increased significantly post vaccination. The plasma level of the transforming growth factor (TGF-β), but not interleukin (IL)-2, IL-4, IL-5, IL-10, IFN-γ, TNF-α, was also found to increase significantly after vaccination. We further correlated the cytokine fold-increases with the anti-influenza antibody titer for individual post vaccination. It was found that the IL-10 level after vaccination correlated with the fold-increases of anti-H1N1, anti-H3N2, anti-B/Yamagata, and anti-B/Victoria antibodies. But, a negative relationship occurs between the TGF-β level and fold-increases of anti-H1N1, anti-H3N2, anti-B/Yamagata, and anti-B/Victoria antibodies post vaccination. Treg cells and TGF-β seem to participate in the downregulation of the anti-influenza antibody response post influenza vaccination. Alteration of Treg activity might enhance influenza vaccine antibody responses and efficacy.

The detailed analysis of the changes of murine dendritic cells (DCs) induced by thymic peptide: pidotimod(PTD)

Xiaofang Hu, Wei Zheng, Lu Wang, Nan Wan, Bing Wang, Weiwei Li, Hui Hua, Xu Hu and Fengping Shan
Pages 1250 - 1258
http://dx.doi.org/10.4161/hv.20579
Abstract | Full Text | PDF

The aim of present research is to analyze the detailed changes of dendritic cells (DCs) induced by pidotimod(PTD). These impacts on DCs of both bone marrow derived DCs and established DC2.4 cell line were assessed with use of conventional scanning electron microscopy (SEM), flow cytometry (FCM), transmission electron microscopy (TEM), cytochemistry assay FITC-dextran, bio-assay and enzyme linked immunosorbent assay (ELISA). We demonstrated the ability of PTD to induce DC phynotypic and functional maturation as evidenced by higher expression of key surface molecules such as MHC II, CD80 and CD86. The functional tests proved the downregulation of ACP inside the DCs, occurred when phagocytosis of DCs decreased, with simultaneously antigen presentation increased toward maturation. Finally, PTD also stimulated production of more cytokine IL-12 and less TNF-α. Therefore it is concluded that PTD can markedly exert positive induction to murine DCs.

Open Access Article

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 years: Phase II randomized controlled trial in Singapore

Yee Sin Leo, Annelies Wilder-Smith, Sophia Archuleta, Lynette P. Shek, Chia Yin Chong, Hoe Nam Leong, Chian Yong Low, May-Lin Helen Oh, Alain Bouckenooghe, T. Anh Wartel and Denis Crevat
Pages 1259 - 1271
http://dx.doi.org/10.4161/hv.21224
Abstract | Full Text | PDF

This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2–11 years) or influenza vaccine for adolescents (12–17 years) and adults (18–45 years). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.

Open Access Article

Individualism, acceptance and differentiation as attitude traits in the public’s response to vaccination

Baruch Velan, Valentina Boyko, Liat Lerner-Geva, Arnona Ziv, Yaakov Yagar and Giora Kaplan
Pages 1272 - 1282
http://dx.doi.org/10.4161/hv.21183
Abstract | Full Text | PDF

The attitude of the general public to vaccination was evaluated through a survey conducted on a representative sample of the Israeli population (n = 2,018), in which interviewees were requested to express their standpoints regarding five different vaccination programs. These included: pandemic influenza vaccination, seasonal influenza vaccination, travel vaccines, Human Papilloma Virus vaccine and childhood vaccinations. Analysis of the responses reveal three major attitude traits: a) acceptance, characterized by the opinion that targets should be vaccinated; b) individualism, characterized by the opinion that vaccination should be left to personal choice; and c) differentiation, characterized by the tendency to express different attitudes when addressing different vaccination programs. Interestingly, direct opposition to vaccination was found to be a minor attitude trait in this survey. Groups within the population could be defined according to their tendency to assume these different attitudes as Acceptors, Judicious-acceptors, Differentiators, Soft-individualists, and Hard-individualists. These groups expressed different standpoints on all five vaccination programs as well as on other health recommendations, such as screening for early detection of cancer. Attitude traits could be also correlated, to a certain extent, with actual compliance with vaccination programs. Interestingly, attitudes to vaccination were not correlated with social profiles related to income or education, although younger individuals exhibited higher degrees of individualism and differentiation. Taken together, all this is in accordance with the current social settings, underlining the individual's tendency for critical evaluation and self-stirring. This should be taken into consideration by health authorities involved in vaccination programs.

Assessment of squalene adjuvanted and non-adjuvanted vaccines against pandemic H1N1 influenza in children 6 months to 17 years of age

Timo Vesikari, Stéphanie Pepin, Inca Kusters, Agnès Hoffenbach and Martine Denis
Pages 1283 - 1292
http://dx.doi.org/10.4161/hv.21265
Abstract | Full Text | PDF

Vaccines were urgently needed in 2009 against A/H1N1 pandemic influenza. Based on the H5N1 experience, it was originally thought that 2 doses of an adjuvanted vaccine were needed for adequate immunogenicity. We tested H1N1 vaccines with or without AF03, a squalene-based adjuvant, in children.

Two randomized, open-label, trials were conducted. Participants 3–17 y received two injections of 3.8 µg or 7.5 µg hemagglutinin (HA) with adjuvant or 15 µg HA without adjuvant. Participants aged 6–35 mo received two injections of 1.9 µg or 3.8 µg HA with full or half dose adjuvant or 7.5 µg HA without adjuvant.

All subjects 3 to 17 y reached seroprotection (hemagglutination inhibition (HI) titer ≥ 40) after the first dose of the adjuvanted vaccine, and 94% and 98% in the 3–8 and 9–17 y groups respectively with the non-adjuvanted vaccine. In children aged 6–35 mo responses were modest after one dose, but after two doses virtually all children were seroprotected regardless of HA or adjuvant dose. In this age group, antibody titers were 5 to 7 times higher after adjuvanted than non-adjuvanted vaccine. The higher responses with the adjuvanted vaccine were also reflected as better antibody persistence. There was no clustering of adverse events that would be suggestive of a safety signal.

While a single injection was sufficient in subjects from 3 y, in children aged 6–35 mo two injections of this A/H1N1 pandemic influenza vaccine were required. Formulation of this vaccine with adjuvant provided a significant advantage for immunogenicity in the latter age group.

Modeling the economic value of a Chagas’ disease therapeutic vaccine

Bruce Y. Lee, Kristina M. Bacon, Angela R. Wateska, Maria Elena Bottazzi, Eric Dumonteil and Peter J. Hotez
Pages 1293 - 1301
http://dx.doi.org/10.4161/hv.20966
Abstract | Full Text | PDF

The health burden of Chagas’ disease (resulting from Trypanosoma cruzi infection) in Latin America (estimated to outweigh that of malaria by 5-fold and affect 2–6 million people in Mexico alone) has motivated development of therapeutic vaccines to prevent infection progression to severe disease. Our economic model for a Chagas’ therapeutic vaccine in Mexico suggests that a vaccine would be highly cost-effective and in many cases economically dominant (providing both cost savings and health benefits) throughout a range of protection durations, severe adverse event risk, and dosing regimens and would be most likely to provide a positive return on investment if the vaccine prevented (rather than delayed) the onset of cardiomyopathy.




COMMENTARIES

Evaluation of autoimmune safety signal in observational vaccine safety studies

Chun Chao and Steven Jacobsen
Pages 1302 - 1304
http://dx.doi.org/10.4161/hv.21268
Abstract | Full Text | PDF

Autoimmune safety evaluation is an important component of post-licensure vaccine safety evaluation. Recently, we published the findings from a large observational safety study of the quadrivalent human papillomavirus vaccine in females. From this study, based on two large managed care organizations, we have obtained some empirical data that may prove useful for the design of future vaccine safety studies within a managed care environment. For autoimmune conditions, a major challenge in vaccine safety study is to determine true incident cases in relation to the timing of vaccination. We found expert case review of medical records an indispensable component for autoimmune safety studies based on electronic health records. Case identification should also be expanded to include the use of laboratory test results or other relevant measures in addition to the disease specific ICD-9 diagnosis codes, when applicable. Furthermore, we recommend the parallel use of both safety signal evaluation that involves pattern evaluation for conditions that are more common, and statistical comparisons for conditions that are rather rare. Finally, we recommend an accompanying vaccine uptake study to understand the potential selection bias and confounding in a given study population that should be addressed with data collection and analytical techniques.

Vaccines against Toxoplasma gondii: Status, challenges and future directions

Qi Liu, Lachhman Das Singla and Huaiyu Zhou
Pages 1305 - 1308
http://dx.doi.org/10.4161/hv.21006
Abstract | Full Text | PDF

Toxoplasma gondii is a ubiquitous protozoan parasite that can infect a wide range of animals including humans. This single known species in the genus Toxoplasma is considered as one of the most successful eukaryotic pathogens which is of major medical and veterinary importance. Effective vaccines may contribute toward preventing and controlling the spread of toxoplasmosis. The present communication addresses the current status of development of vaccines against T. gondii. Further discussion is made on the difficulties along with challenges, such as vaccine construct, mode of vaccine administration and standardization of immunization evaluation. Finally suggestions are made on possible directions for future research on the development of vaccines against T. gondii.

Personalized peptide vaccination: A novel immunotherapeutic approach for advanced cancer

Tetsuro Sasada, Masanori Noguchi, Akira Yamada and Kyogo Itoh
Pages 1309 - 1313
http://dx.doi.org/10.4161/hv.20988
Abstract | Full Text | PDF

Since both tumor cells and immune cell repertoires are diverse and heterogeneous, immune responses against tumor-associated antigens might be substantially different among individual patients. Personalized selection of right peptides for individuals could thus be an appropriate strategy for cancer vaccines. We have developed a novel immunotherapeutic approach, personalized peptide vaccination (PPV), in which HLA-matched peptides are selected and administered, based on the pre-existing host immunity before vaccination. Recent clinical trials of PPV have demonstrated a feasibility of this new therapeutic approach in various types of advanced cancers. For example, a randomized phase II trial for patients with castration resistant prostate cancer showed a possible clinical benefit in the PPV group. In the patients undergoing PPV, lymphocyte counts, increased IgG responses to the vaccine peptides, and inflammatory factors in pre-vaccination peripheral blood might be potential biomarkers for prognosis. Further randomized phase III trials would be recommended to prove clinical benefits of PPV.

Pentavalent vaccine: A major breakthrough in India’s Universal Immunization Program

Mohan Bairwa, Manju Pilania, Meena Rajput, Pardeep Khanna, Neelam Kumar, Mukesh Nagar and Sumit Chawla
Pages 1314 - 1316
http://dx.doi.org/10.4161/hv.20651
Abstract | Full Text | PDF

Immunization is one of the most important public health interventions and a cost effective strategy to control the infectious diseases especially in children. Complete immunization coverage in India has increased from below 20% in the 1980s to nearly 61% at present, but still more than 1/3rd children remain un-immunized. Advent of combination vaccines has facilitated incorporation of additional vaccines into immunization schedule. Pentavalent vaccine, against five killer diseases–diphtheria, pertussis, tetanus, hepatitis B and Hemophilus influenza type B (Hib), has been introduced in almost all GAVI eligible countries by 2011. Government of India introduced the vaccine in two states in pilot phase and has given green signal to six more states. The use of pentavalent vaccine automatically raises the coverage level of hepatitis B and Hib vaccines. If the vaccines are provided individually, the coverage of hepatitis B and Hib vaccines usually lags behind DPT coverage. This gap can be filled by using pentavalent vaccine in routine immunization programmes.

Pneumococcal conjugate vaccine: A newer vaccine available in India

Ramesh Verma and Pardeep Khanna
Pages 1317 - 1320
http://dx.doi.org/10.4161/hv.20654
Abstract | Full Text | PDF

Streptococcus pneumoniae, or “pneumococcus,” causes pneumonia and infections of the brain and blood that are responsible for significant mortality in children under five years as well as in the elderly. Pneumococcal diseases are a major public health problem worldwide. S. pneumoniae is responsible for 15–50% of all episodes of community-acquired pneumonia, 30–50% of all cases of acute otitis media, and a significant proportion of bacterial meningitis and bacteremia. S. pneumoniae kills at least one million children under the age of five every year, which is more than malaria, AIDS and measles combined. More than 70% of the deaths are in developing countries. In 2007, pneumococcal pneumonia was the leading infectious killer of children worldwide. Perhaps more importantly, pneumonia remains the leading killer of children in India. A recent UNICEF publication estimated that 410,000 children under age 5 y die of pneumonia each year in India, and recent data shows that an estimated 25% of all child deaths in India are due to pneumonia. The fact that this high burden of pneumonia has remained undiminished in India in spite of economic growth and decline in child mortality due to other diseases is a reminder of the importance of tackling pneumonia head-on with dedicated resources. The burden of pneumococcal meningitis, which constitutes about half of all childhood meningitis cases in most settings and a greater proportion of meningitis deaths, makes it difficult to avoid the conclusion that the pneumococcus is responsible for 1 million child deaths each year. Global Alliance for Vaccine and Immunization (GAVI) has offered to supply PCV at a cost of 0.15–0.30 USD/dose to India for inclusion in the national immunization schedule and commits to extending this support until the year 2015. Pneumococcal vaccination in not recommended in children aged 5 and above.

Open Access Article

In Memoriam: Dr H. Fred Clark (1937–2012)

Paul Offit, Frederick Murphy and Stanley Plotkin
Pages 1321 - 1322
http://dx.doi.org/10.4161/hv.21856
Abstract | Full Text | PDF

Dr H. Fred Clark, a colleague and friend, passed away on April 28, 2012. Drs Frederick Murphy, Stanley Plotkin, and Paul Offit, who knew Fred at different stages of his career, recall his life.

Open Access Article

Dendritic cell-based in vitro assays for vaccine immunogenicity

Rob J. Vandebriel and Marcel H.N. Hoefnagel
Pages 1323 - 1325
http://dx.doi.org/10.4161/hv.21350
Abstract | Full Text | PDF

Dendritic cells (DC) are pivotal in the induction of adaptive immune responses because they can activate naive T-cells. Moreover, they steer these adaptive immune responses by integrating various stimuli, such as from different pathogen associated molecular patterns and the cytokine milieu. Immature DC are very well capable of ingesting protein antigens, whereas mature DC are efficient presenters of peptides to naive T cells. Human DC can be readily cultured from peripheral blood mononuclear cells, which are isolated from human blood. There is a strong need to monitor in a high-throughput fashion the immunogenicity of candidate vaccines during the process of vaccine development. Furthermore, regulators require efficacy and safety testing for batch release. For some vaccines, these tests require animal testing, causing pain and discomfort, which cannot be contested because it would interfere with the test results. With the aims of promoting vaccine development and reducing the number of animals for batch release testing, we propose to use more broadly human DC for vaccine immunogenicity testing. In this commentary, this proposition is illustrated by several examples in which the maturation of human DC was successfully used to test for vaccine and adjuvant immunogenicity.





Cancer Commentary Series

SPECIAL FOCUS REVIEW

Reimbursement challenges with cancer immunotherapeutics

Alex Kudrin
Pages 1326 - 1334
http://dx.doi.org/10.4161/hv.20550
Abstract | Full Text | PDF

Today the task of cancer vaccine developers is not only to excel in cancer immunology and art of conducting immunotherapy trials but also in the analysis and forecasting the cost-effectiveness of the final product. This article reviews methodology used by EU health-technology bodies in the appraisal of new therapies based on economic and clinical values and different budgetary uncertainties. Increasingly, new oncology treatments were able to access EU market only under provision of risk-sharing agreements with payers and examples of such agreements are given here. Cancer vaccine developers should consider early collection of patient reported outcomes in order to project additional clinical and economic value with immunotherapy. Furthermore, early interaction with different stakeholders including patient organizations, physicians and payer bodies can facilitate market access.

SPECIAL FOCUS COMMENTARIES

Overview of cancer vaccines: Considerations for development

Alex Kudrin
Pages 1335 - 1353
http://dx.doi.org/10.4161/hv.20518
Abstract | Full Text | PDF

Cancer immunotherapy has seen a tremendous number of failures and only few recent regulatory successes. This is a review dedicated to determine major regulatory and developmental issues around cancer immunotherapeutics. A three pillar approach should be used in setting a development path: discovery platforms and sufficient pool of validated tumor antigens, product development strategy enabling to bring the product closer to the patient and clinical development strategy accounting for competitive landscape, treatment paradigm, technical and commercial risks. Regulatory framework existing around cancer vaccines in the EU, US, Japan and some developing countries is outlined. In addition, the review covers some specific issues on the design and conduct of clinical trials with cancer vaccines.

Cancer immunotherapy products: Regulatory aspects in the European Union

Jorge Camarero and Sol Ruiz
Pages 1354 - 1359
http://dx.doi.org/10.4161/hv.21142
Abstract | Full Text | PDF

Active immunotherapy products (widely known as “cancer vaccines”) are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications. Some of these aspects are discussed in this paper in relationship with the regulatory requirements in the European Union and as applied to two recently assessed medicinal products, Oncophage and Provenge, both considered therapeutic “cancer vaccines” for renal cell carcinoma and prostate cancer, respectively.

Cancer vaccines and immunotherapeutics: Challenges for pricing, reimbursement and market access

Bengt Jönsson and Nils Wilking
Pages 1360 - 1363
http://dx.doi.org/10.4161/hv.21921
Abstract | Full Text | PDF

Public payment is key to market access for new therapeutics including cancer vaccines and cancer immunotherapeutics. However, the methodology for economic evaluation aimed at informing decisions about pricing and reimbursement is different for cancer vaccines, such as HPV for preventing the occurrence or incidence of cancer, and immunotherapeutics for treatment of patients with manifest cancer. Vaccination against HPV is a traditional public health intervention, where the role of economic evaluation is to inform decisions about optimal vaccination strategies. The decision is about funding for a vaccination program, aimed at vaccinating a defined population at risk, either at a national or regional level. The methodology of economic evaluation is based on statistical modeling of number of cases prevented over a long time period, and the costs and health outcome related to this, for different vaccination strategies

For immunotherapeutics, the role of economic evaluation is to assist decisions about reimbursement and guidelines for treatment of patients with establish disease, very often at advanced stages with short life expectancy. The focus is on alternative treatment options, and the costs and outcomes associated with these. Alternatives may be best supportive care, immunotherapeutics or other treatments like surgery, radiotherapy and other anti-cancer drugs. From an economic perspective the type of therapy does not matter, only costs and outcome associated with the relevant alternatives. The main controversy about reimbursement of immunotherapeutics, as with other new cancer drugs, has been the cost of treatment, mainly determined by the price of the therapy, in relation to the expected benefits in terms of survival and quality of life. This paper reviews the evidence on cost-effectiveness, the reimbursement decisions made, and the impact on market access for new immunotherapeutics. Sipuleucel-T (Provenge^®) and abiraterone (Zytiga^®) for treatment of prostate cancer and ipilimumab (Yervoy^®) as well as vemurafenib (Zelboraf^®) for treatment of metastatic melanoma are used as examples of the economic issues involved in analysis and decision-making.