Table of Contents

Volume 8, Issue 8

  August 2012

  Pages 1013 - 1165

Special Focus: Cancer Commentary Series Guest Editors: Michael G. Hanna and Alex Kudrin

 

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EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald Ellis and Eva M. Riedmann
Page 1013
http://dx.doi.org/10.4161/hv.21698
Full Text | PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 1014 - 1017
http://dx.doi.org/10.4161/hv.21700
Abstract | Full Text | PDF

Two new combination pediatric vaccines advancing to use in infants
Oncolytic viruses successfully delivered intravenously
Cuba eliminates hepatitis B among minors under 15
Alzheimer's vaccine trial a success
Study: Shingles vaccine safe for patients on immune-suppressing drugs
Therapeutic cancer vaccine against metastatic renal cell carcinoma enters Phase 3
Pfizer’s Men B vaccine shows promise in Phase 2
Biovest initiates formal regulatory approval process for BiovaxID in Europe




PORTRAIT

Open Access Article

Portrait of a Leader in Immunotherapeutics: Oncolytic viruses for treatment of cancer

Akseli Hemminki
Pages 1018 - 1021
http://dx.doi.org/10.4161/hv.21699
Abstract | Full Text | PDF

When I heard about the concept of immunotherapeutics, I immediately loved it. Everything I had learned about medicine, cancer biology, genetics and oncology indicated to me that this was a potent approach, and at the time, completely untapped. I figured that since we had been unable to cure most metastatic solid tumors, something completely different needed to be employed. Realistically, “magic bullets” are not easy to find and therefore something that can be combined with other therapies, for enhanced synergy without overlapping adverse events, would be appealing.




REVIEWS

New insights into rotavirus vaccines

Chiara Mameli, Valentina Fabiano and Gian Vincenzo Zuccotti
Pages 1022 - 1028
http://dx.doi.org/10.4161/hv.20295
Abstract | Full Text | PDF

Rotavirus vaccines have shown to be effective and well tolerated in clinical trials. However it’s crucial to point out that immunization occurs in “real-word” conditions different from ideal clinical trial settings. Thus, the impact of rotavirus vaccines in terms of effectiveness and safety needs to be evaluated in real-world conditions. Post-licensure data regarding vaccine impact, effectiveness and safety under routine use are now available and provide a “real-world view.”

Open Access Article

Importance of circulating antibodies in protection against meningococcal disease

Kim S. Erlich and Blaise L. Congeni
Pages 1029 - 1035
http://dx.doi.org/10.4161/hv.20473
Abstract | PDF

Neisseria meningitidis infection results in life-threatening illnesses, including bacteremia, sepsis and meningitis. Early diagnosis and treatment are a challenge due to rapid disease progression, resulting in high mortality and morbidity in survivors. Disease can occur in healthy individuals, however, risk of infection is higher in patients with certain risk factors. N meningitidis carriage and case-fatality rates are high in adolescents and young adults. The absolute incidence of meningococcal disease has decreased partially due to increasing meningococcal vaccination rates. Maintaining protective levels of circulating antibodies by vaccination is necessary for clinical protection against disease. The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices guidelines recommend vaccination for all individuals aged 11 through 12 years, followed by a booster dose at age 16 years for maintenance of protective antibody levels throughout the high-risk years. Despite these guidelines, many adolescents remain unvaccinated and susceptible to infection and disease. 





SHORT REPORTS

Open Access Article

Immunogenicity and safety of measles-mumps-rubella and varicella vaccines coadministered with a fourth dose of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in toddlers: A pooled analysis of randomized trials

Kristina A. Bryant, Jodie McVernon, Colin D. Marchant, Terry Nolan, Gary S. Marshall, Peter Richmond, Helen Marshall, Michael Nissen, Stephen B. Lambert, Emmanuel Aris, Narcisa Mesaros and Jacqueline M. Miller
Pages 1036 - 1041
http://dx.doi.org/10.4161/hv.20357
Abstract | Full Text | PDF

A pooled analysis was conducted of 1257 toddlers who received a fourth dose of Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) or Hib conjugate vaccine (Hib polysaccharide conjugated to N. meningitidis outer membrane protein) coadministered with measles-mumps-rubella (MMR) and varicella (VAR) vaccines (NCT00134719/NCT00289783). Noninferiority of immunological responses to MMR and VAR was demonstrated between groups and incidences of MMR- and VAR-specific solicited symptoms were similar, indicating that HibMenCY-TT can be coadministered with MMR and VAR.

Open Access Article

TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults

Rasmus Offersen, Jesper Melchjorsen, Søren R. Paludan, Lars Østergaard, Martin Tolstrup and Ole S. Søgaard
Pages 1042 - 1047
http://dx.doi.org/10.4161/hv.20707
Abstract | Full Text | PDF

HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/− a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response.

Phase 4 randomized trial of intradermal low-antigen-content inactivated influenza vaccine vs. standard-dose intramuscular vaccine in HIV-1-infected adults

Filippo Ansaldi, Laura Valle, Daniela de Florentiis, Valentina Parodi, Giuseppe Murdaca, Bianca M. Bruzzone, Paolo Durando, Maurizio Setti and Giancarlo Icardi
Pages 1048 - 1052
http://dx.doi.org/10.4161/hv.20347
Abstract | Full Text | PDF

This study evaluated safety, tolerability and immunogenicity of intradermal (ID) trivalent inactivated split influenza vaccine, with a lower antigen content (9 µg HA per strain) than the conventional intramuscular one (15 µg), in HIV-1-infected adults younger than 60 y. A total of 54 HIV-1-positive participants were enrolled and randomly assigned to receive a single dose of either ID-administered low-antigen-content split inactivated vaccine or intramuscularly-administered (IM) standard-dose inactivated split vaccine. Subjects were provided with a diary to monitor any local and/or systemic reactions to the vaccine for 7 d following vaccination. Serum samples were collected before, 28 d and 90 d after immunization. The plasma HIV-RNA and CD4⁺ T-lymphocyte count were checked at day 0 and day 90. Serum hemagglutination-inhibition (HI) activity for the three influenza strains included in the vaccine composition was measured to assess the antibody response at one month and 3 mo after vaccination. Both vaccines showed optimal safety and tolerability profiles. All the three Committee for Medicinal Products for Human Use immunogenicity criteria for vaccine approval in adults younger than 60 were met by both vaccines against A(H1N1) and A(H3N2) viruses. Both vaccines met mean-fold-increase and seroprotection criteria but failed seroconversion criteria against B virus. No difference in terms of post-vaccination geometric mean titers, mean fold increase, seroprotection and seroconversion rates were found comparing ID and IM vaccines. In conclusion, the recently available low-antigen-content ID vaccine is safe, well-tolerated and as immunogenic as IM standard-dose influenza vaccine.




RESEARCH PAPERS

Host responses to live-attenuated Venezuelan equine encephalitis virus (TC-83): Comparison of naïve, vaccine responder and nonresponder to TC-83 challenge in human peripheral blood mononuclear cells

Rebecca A. Erwin-Cohen, Aimee I. Porter, Phillip R. Pittman, Cynthia A. Rossi and Luis DaSilva
Pages 1053 - 1065
http://dx.doi.org/10.4161/hv.20300
Abstract | Full Text | PDF

Venezuelan equine encephalitis virus (VEEV) is a positive-strand RNA Alphavirus endemic in Central and South America, and the causative agent of fatal encephalitis in humans. In an effort to better understand the mechanisms of infection, including differences between people who produce a neutralizing antibody response to the vaccine and those who do not, we performed whole genome transcriptional analysis in human PBMCs exposed in vitro to the live-attenuated vaccine strain of VEEV, TC-83. We compared the molecular responses in cells from three groups of individuals: naïve; previously vaccinated individuals who developed a neutralizing antibody response to the vaccine (responders); and those who did not develop a neutralizing antibody response to the vaccine (nonresponders). Overall, the changes in gene expression were more intense for the naïve group after TC-83 challenge and least potent in the nonresponder group. The main canonical pathways revealed the involvement of interferon and interferon-induced pathways, as well as toll-like receptors TLR- and interleukin (IL)-12-related pathways. HLA class II genotype and suppression of transcript expression for TLR2, TLR4 and TLR8 in the nonresponder group may help explain the lack of vaccine response in this study group. Because TL3 and TLR7 transcripts were elevated in all study groups, these factors may be indicators of the infection and not the immunological state of the individuals. Biomarkers were identified that differentiate between the vaccine responder and the vaccine nonresponder groups. The identified biomarkers were contrasted against transcripts that were unique to the naïve population alone upon induction with TC-83. Biomarker analysis allowed for the discernment between the naïve (innate) responses; the responder (recall) responses; and the nonresponder (alternative) changes to gene transcription that were caused by infection with TC-83. The study also points to the existence of HLA haplotypes that may discriminate between vaccine low- and high-responder phenotypes.

Open Access Article

Size of clinical trials and Introductory prices of prophylactic vaccine series

Steven H. Weinberg, Amy T. Butchart and Matthew M. Davis
Pages 1066 - 1070
http://dx.doi.org/10.4161/hv.20506
Abstract | Full Text | PDF

Costs of completing the recommended immunization schedule have increased over the last decade. Access to prophylactic vaccines may become limited due to financing obstacles within current delivery systems. Vaccine prices reflect research and development expenses incurred by vaccine manufacturers, including costs associated with evaluating candidate vaccines in human subjects. If the number of subjects in clinical trials is increasing over time and associated with vaccine price, this may help explain increases in prices of vaccine series. We examined whether: (A) the initial public- and private-sector prices for recommended prophylactic vaccine series licensed and recommended in the US increased from 2000–2011, (B) the number of human subjects per licensed vaccine increased during the time period, and (C) the number of human subjects was associated with the initial public–and private–sector prices of the vaccine series. In regression analyses of 13 vaccines, approval year was not significantly associated with the number of human subjects, initial public-sector prices, or initial private-sector prices. While the number of phase II subjects was not significantly associated with prices, the numbers of phase III and combined late phase (phases II + III) subjects were significantly associated with initial public- and private-sector series prices (p < 0.05). The association between number of subjects and initial prices demonstrated diminishing marginal increases in price with increasing numbers of subjects. These findings may help guide the number of subjects required by the FDA in clinical trials, in order to reduce expenses for manufacturers and thereby help mitigate increases in initial vaccine series prices.

Comparison of long-term immunogenicity (23 y) of 10 μg and 20 μg doses of hepatitis B vaccine in healthy children

Qian Wu, Gui-hua Zhuang, Xue-liang Wang, Tie-jun Hou, Dimpy P. Shah, Xiao-li Wei, Li-rong Wang and Min Zhang
Pages 1071 - 1076
http://dx.doi.org/10.4161/hv.20656
Abstract | Full Text | PDF

To compare the long-term immunogenicity and seroprotection rates in healthy children following 23 years of vaccination with 10 μg or 20 μg doses of plasma-derived hepatitis B vaccine, we revisited all participants from our previous randomized controlled trial. At year 23, 81 participants were tested for HBV serological markers and HBV-DNA, and a booster dose was given to those with anti-HBs titer < 10 mIU/mL. After eliminating the interference of a Year 11 booster dose and vaccines received outside of the trial, around 50% of participants still maintained anti-HBs titers ≥ 10 mIU/mL in both 10 μg and 20 μg groups (p > 0.05). The peak immune response of vaccination (anti-HBs antibody levels at 12 mo after 1st vaccine dose) and Year 11 anti-HBs levels were significantly associated with Year 23 seroprotection rates. Most of the participants in both groups, regardless of their prior immune status, developed a rapid and robust anamnestic antibody response after the booster dose at year 23. No case of clinically significant HBV infection was observed during the entire study period of 23 y with only one transient HBsAg seroconversion in 10 μg vaccine group. We concluded that seroprotection provided by 10μg or 20 μg doses of hepatitis B vaccine persists for 23 years in more than half of vaccinated individuals in highly HBV-endemic areas, irrespective of 10 μg or 20 μg vaccine doses. Future studies with larger sample sizes comparing long-term efficacy of various doses of plasma-derived and recombinant HBV vaccines are recommended.

Evaluation of a one week intradermal regimen for rabies post-exposure prophylaxis: Results of a randomized, open label, active-controlled trial in healthy adult volunteers in India

Mysore Kalappa Sudarshan, Doddabele Hanumanthaiah Ashwath Narayana, Shampur Narayan Madhusudana, Ramesh Holla, Belludi Yajaman Ashwin, Bilagumba Gangaboraiah and Haradanahalli S. Ravish
Pages 1077 - 1081
http://dx.doi.org/10.4161/hv.20471
Abstract | Full Text | PDF

The currently recommended intradermal regimen for post-exposure prophylaxis spreads over a month period which many times lead to low compliance from the patients. There is a need to introduce and evaluate short course regimens to overcome this problem. This study was conducted to evaluate the immunogenicity and safety of a “new one week intradermal regimen” for rabies post-exposure prophylaxis. A total of 80 healthy adult volunteers were enrolled and allocated randomly either to purified chick embryo cell (PCECV) rabies vaccine or purified verocell rabies vaccine (PVRV), 40 in each group. Each subject received intradermally one of the vaccines, using the one week regimen (4–4-4). Blood samples were collected on Days 0, 7, 14, 28,180 and 365 for estimation of rabies virus neutralizing antibody (RVNA) concentration. The sera samples were analyzed by rapid fluorescent focus inhibition test (RFFIT). All subjects in both the groups had adequate RVNA concentration of ≥ 0.5 IU/mL from day 14 to till day 180 and the difference of geometric mean concentrations between the two groups was not significant (p > 0.606). Further to assess the immunological memory produced by this new regimen, a “single visit four site” intradermal booster vaccination was given to those who did not have adequate RVNA concentration on day 365. This resulted in a quick and enhanced RVNA concentration in these subjects thus denoting a successful anamnestic response. The incidence of adverse events was 8.3% in PCECV group and 1.6% in PVRV group (p = 0.001) and the regimen was well tolerated without any dropouts. In conclusion, the new “one week intradermal regimen” is immunogenic and safe for rabies post-exposure prophylaxis and needs to be further evaluated in persons exposed to rabies.

Comparison of stimulating effect on subpopulations of lymphocytes in human peripheral blood by methionine enkephalin with IL-2 and IFN-γ

Hui Hua, Changlong Lu, Weiwei Li, Jingjuan Meng, Danan Wang, Nicolas P. Plotnikoff, Enhua Wang and Fengping Shan
Pages 1082 - 1089
http://dx.doi.org/10.4161/hv.20759
Abstract | Full Text | PDF

The aim of this study was to investigate the effects of mechanisms of methionine enkephalin (MENK) on lymphocytes in human peripheral blood. We detected CD4+T cells, CD8+T cells, CD4+CD25+ regulatory T cells (Treg), dendritic cells (DCs), natural killer cells (NK), NKT cells and γδT cells before and after treatment with 10⁻¹²M MENK, in cell culture by FCM and RT-PCR. Our findings show that MENK stimulating expansion of lymphocyte subpopulationns by inhibiting CD4+CD25+ regulatory T cells (Treg), which is unique discovery of our study. We may use MENK as a drug to treat cancer patients, whose immune systems are damaged by chemotherapy or radiotherapy.

Yeast expressed foldable quadrivalent Aβ15 elicited strong immune response against Aβ without Aβ-specific T cell response in wild C57BL/6 mice

Lin Tan, Hao Wang, Xin Tan, Juntao Zou and Zhibin Yao
Pages 1090 - 1098
http://dx.doi.org/10.4161/hv.20472
Abstract | Full Text | PDF

Active and passive immunizations with Aβ and Aβ antibodies successfully reduced AD pathology and improved cognitive functions in an AD mouse model. However, human clinical trials of vaccination with synthetic Aβ(AN1792), were halted due to brain inflammation, presumably induced by T cell-mediated immune response. In this study, we used Picha pastoris to produce a recombinant peptide vaccine, r4 × Aβ15(recombinant 4 × Aβ15), four tandem repeats of Aβ(1-15) interlinked by spacers . Wild-type mice were injected subcutaneously with CFA/IFA as adjuvant. r4 × Aβ15 vaccine elicited high titer anti-Aβ antibodies which bound to Aβ plaque in brain tissue from Tg2576 mouse. The antibody isotype was mainly IgG(1), indicating anti-inflammatory Th2 type. There was no splenocyte proliferation against Aβ peptide, which indicates that the r4 × Aβ15 vaccine does not induce Aβ-specific T cellular immune response. Thus, r4 × Aβ15 vaccine may be a safe and efficient vaccine for AD.

Model-based projections of the population-level impact of hepatitis A vaccination in Mexico

Thierry Van Effelterre, Rodrigo De Antonio-Suarez, Adrian Cassidy, Luis Romano-Mazzotti and Cinzia Marano
Pages 1099 - 1108
http://dx.doi.org/10.4161/hv.20549
Abstract | Full Text | PDF

There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic.

This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology. It was calibrated using Mexican age-specific seroprevalence and symptomatic HAV incidence data.

With 70% first-dose coverage and 85% second-dose coverage, the calibrated model projected that HAV vaccination would reduce the incidence of all HAV infections (symptomatic and asymptomatic) after the first 25 y of vaccination by 71–76% (minimum and maximum for different transmission scenarios). The projected reduction in cumulative incidence of symptomatic HAV infections over the first 25 y of vaccination was 45–51%. With 90% first-dose coverage and 85% second-dose coverage, the projected reduction in incidence of all HAV infections was 85–93%, and the projected reduction in the cumulative incidence of symptomatic HAV infections was 61–67%, over a 25-y time frame. Sensitivity analyses indicated that second-dose coverage is important under the conservative base-case assumptions made about the duration of vaccine protection.

The model indicated that universal infant HAV vaccination could substantially reduce the burden of HAV disease in Mexico.

Lot-to-lot consistency study of the fully liquid pentavalent DTwP-HepB-Hib vaccine Quinvaxem^® demonstrating clinical equivalence, suitability of the vaccine as a booster and concomitant administration with measles vaccine

Sanet Aspinall, Deirdre Traynor, Philip Bedford and Katharina Hartmann
Pages 1109 - 1118
http://dx.doi.org/10.4161/hv.21095
Abstract | Full Text | PDF

This double-blind, randomized study evaluated the immunogenicity and safety of three production lots of the fully liquid combination DTwP-Hep-Hib vaccine, Quinvaxem^® (Crucell, The Netherlands) in 360 healthy infants aged 42–64 d old given at 6, 10 and 14 weeks of age (Core Study). The Core Study was followed by an open-label Booster Phase evaluating immunogenicity and safety of a booster dose of Quinvaxem^® given with either concomitant or deferred measles vaccine in 227 infants who completed the Core Study. One month after the third dose of Quinvaxem^® immune responses reflecting seroprotection or seroconversion were observed in more than 90% of infants for all three vaccine lots. Quinvaxem^® elicited a strong booster response as demonstrated by a large increase in antibodies against all antigens, which appeared to be unaffected by concomitant administration of the measles vaccine. Safety results were in line with previous reports for Quinvaxem^® with no unexpected adverse events (AEs) being reported. In the Core Study and Booster Phase, Quinvaxem^® was well tolerated. No study vaccine-related serious AEs were reported. Thus, Quinvaxem^® was immunogenic and well-tolerated when administered to infants according to a 6–10–14 week vaccination schedule. The three production lots had consistent reactogenicity and immunogenicity profiles. The booster dose of Quinvaxem^® was also immunogenic and safe, regardless of whether a monovalent measles vaccine was administered concomitantly or one month later.

NOTE: Correction published in April 2013, Volume 9, Issue 4:
www.landesbioscience.com/journals/vaccines/article/24580/

Open Access Article

Evaluation of immune response following one dose of an AS03_A-adjuvanted H1N1 2009 pandemic influenza vaccine in Japanese adults 65 years of age or older

Hideyuki Ikematsu, Kazuyoshi Tenjinbaru, Ping Li, Anuradha Madan and David Vaughn
Pages 1119 - 1125
http://dx.doi.org/10.4161/hv.21081
Abstract | Full Text | PDF

Objective: This study assessed the immunogenicity, long-term persistence of immune response and safety of a single dose of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (α-tocopherol and squalene based oil-in-water emulsion Adjuvant System) in subjects ≥ 65 y of age (NCT01114620).
Results: At Day 21, the HI immune response met all three European guidance criteria [seroconversion rate (SCR): 60.0%; seroprotection rate (SPR): 64.0%; geometric mean fold rise (GMFR): 10.2] and the US guidance criterion for SCR. At month 6, the HI immune response against the A/California/07/2009 H1N1 strain persisted but at levels lower than that observed at Day 21 (SCR: 38.8%; SPR: 42.9%; HI antibody geometric mean titer: 27.6); the European regulatory guidance criteria for SCR and GMFR were still met. Overall, the vaccine was well-tolerated.
Conclusion

A single dose of the 3.75µg HA AS03-adjuvanted H1N1 2009 pandemic vaccine induced immune responses against the vaccine strain that met the European regulatory guidance criteria at day 21 in the elderly Japanese population; the immune response persisted at lower levels at month 6. No safety concerns were identified. These results suggest that two vaccine doses might be useful for the elderly population to improve antibody induction and persistence.

Methods: In this open-label, single group study, 50 subjects received one dose of the 3.75 µg hemagglutinin (HA) AS03-adjuvanted H1N1 2009 vaccine. Immunogenicity assessments were made before vaccination, 21 days and six months after vaccination using hemagglutination inhibition (HI) and microneutralization assays. Immunogenicity end points were based on US and European regulatory criteria.




COMMENTARIES

Open Access Article

Military vaccines in today’s environment

Connie S. Schmaljohn, Leonard A. Smith and Arthur M. Friedlander
Pages 1126 - 1128
http://dx.doi.org/10.4161/hv.20503
Abstract | Full Text | PDF

The US military has a long and highly distinguished record of developing effective vaccines against pathogens that threaten the armed forces. Many of these vaccines have also been of significant benefit to civilian populations around the world. The current requirements for force protection include vaccines against endemic disease threats as well as against biological warfare or bioterrorism agents, to include novel or genetically engineered threats. The cost of vaccine development and the modern regulatory requirements for licensing vaccines have strained the ability of the program to maintain this broad mission. Without innovative vaccine technologies, streamlined regulatory strategies, and coordinating efforts for use in civilian populations where appropriate, the military vaccine development program is in jeopardy.

India is on the way forward to maternal and neonatal tetanus elimination!

Mohan Bairwa, Shashikantha S.K., Meena Rajput, Pardeep Khanna, Jagbir Singh Malik and Mukesh Nagar
Pages 1129 - 1131
http://dx.doi.org/10.4161/hv.20262
Abstract | Full Text | PDF

Tetanus is an acute, potentially fatal disease, caused by a bacterium, Clostridium tetani. The disease usually occurs in newborns through infection of the unhealed umbilical stump, particularly when the stump is cut with a non-sterile instrument. NT contributes to 5–7% of neonatal mortality worldwide. Several thousand mothers are also estimated to die annually of maternal tetanus. MNT elimination relies on promotion of maternal tetanus immunization along with safe delivery and avoidance of unsafe abortion and umbilical cord care practices. The Government of India (1983) introduced at least two doses of tetanus toxoid vaccine (TT) to all pregnant women during each pregnancy as a part of its nationwide immunization policy. To date, a total of 15 States including union territories of the India have achieved NT elimination. The remaining Indian States need to strengthen TT coverage to save the lives of neonates as well as mothers from tetanus.

Hepatitis A vaccine should receive priority in National Immunization Schedule in India

Ramesh Verma and Pardeep Khanna
Pages 1132 - 1134
http://dx.doi.org/10.4161/hv.20475
Abstract | PDF

Hepatitis A is an acute, usually self-limiting infection of the liver caused by a virus known as hepatitis A virus (HAV). Humans are the only reservoir of the virus; transmission occurs primarily through the fecal-oral route and is closely associated with poor sanitary conditions. The virus has a worldwide distribution and causes about 1.5 million cases of clinical hepatitis each year. The risk of developing symptomatic illness following HAV infection is directly correlated with age. As many 85% of children below 2 y and 50% of those between 2–5 y infected with HAV are anicteric, and among older children and adults, infection usually causes clinical disease, with jaundice occurring in more than 70% of cases. The infection is usually self-limiting with occasional fulminant hepatic failure and mortality. In most developing countries in Asia and Africa, hepatitis A is highly endemic such that a large proportion of the population acquires immunity through asymptomatic infection early in life. HAV is endemic in India; most of the population is infected asymptomatically in early childhood with life-long immunity. Several outbreaks of hepatitis A in various parts of India have been recorded in the past decade such that anti-HAV positivity varied from 26 to 85%. Almost 50% of children of ages 1–5 y were found to be susceptible to HAV. Any one of the licensed vaccines may be used since all have nearly similar efficacy and safety profiles (except for post-exposure prophylaxis / immunocompromised patients, where only inactivated vaccines may be used). Two doses 6 mo apart are recommended for all vaccines. All Hepatitis A vaccines are licensed for use in children aged 1 y or older. However in the Indian scenario, it is preferable to administer the vaccines at age 18 mo or more when maternal antibodies have completely declined. Vaccination at this age is preferable to later since it is easier to integrate with the existing schedule, protects those who have no antibodies, and protects children by the time they attend day care. In India the vaccine against hepatitis A is available for the people who can afford it, but the government of India should give this vaccine as a priority in the national immunization schedule.





Cancer Commentary Series

SPECIAL FOCUS COMMENTARIES

Overview of the cancer vaccine field: Are we moving forward?

Alex Kudrin and Michael G. Hanna, Jr
Pages 1135 - 1140
http://dx.doi.org/10.4161/hv.20474
Abstract | Full Text | PDF

Cancer immunotherapy has seen a tremendous number of failures and only few recent regulatory successes. This review is a first in a series dedicated to evaluate the status of current global clinical pipeline for cancer vaccines. Apart from specific areas of medical need which can be addressed by cancer vaccines, the analysis of the pipeline by clinical indication suggests that a disproportionately large number of candidates is currently developed in prostate, breast, lung cancer and melanoma with significant gap of candidates in remaining oncology indications. With potential offering and benefits that cancer immunotherapy could bring to patient community and society as a whole, we require new innovative R&D, improved Antigen Discovery programs and business models to fill serious gaps in cancer vaccine R&D pipeline.

Biological heterogeneity of cancer

Isaiah J. Fidler
Pages 1141 - 1142
http://dx.doi.org/10.4161/hv.19643
Abstract | Full Text | PDF

Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the continuous growth of metastases that are resistant to conventional therapies. In a large number of cancer patients, metastasis may well have occurred by the time of diagnosis. The metastases can be located in different distant organs and in different regions within a single organ. The major obstacle for the eradication of metastases is the biologic heterogeneity of tumor cells that constitute primary cancers and metastases. Specifically, by the time of diagnosis, malignant neoplasms contain multiple cell populations with diverse biological heterogeneity in growth rate, karyotype, cell surface receptors, antigenicity, immunogenicity, maker enzymes, gene expression, sensitivity to different cytotoxic drugs, invasion, and metastasis. This biologic heterogeneity is not restricted to primary lesions. The cellular composition of metastases in the same organ or in different organs is heterogeneous, both within a single metastasis (intralesional heterogeneity) and among different metastases (interlesional heterogeneity). This heterogeneity is due to two major processes: the selective nature of the metastatic process, and the rapid evolution and phenotypic diversification of clonal tumor cell populations during progressive tumor growth resulting from inherent genetic and epigenetic instability of many clonal populations of tumor cells.

Inter-tumor heterogeneity

Mike Cusnir and Ludmila Cavalcante
Pages 1143 - 1145
http://dx.doi.org/10.4161/hv.21203
Abstract | Full Text | PDF

Advances in the molecular study of cancer have focused on biomarkers in the setting of tumor-driving mutations within the great heterogeneity of the tumor genomic landscape. It is clearly recognized now that even two tumors originating from the same organ even if histological they appear similar their behavior and response to therapy can be different. These findings have increased interest and research to find truly prognostic and predictive biomarkers to serve as tools in better assessing the natural course of disease and response to treatments in the hope of truly individualizing cancer therapy in the future.

A tale of two pities: Autologous melanoma vaccines on the brink

David Berd
Pages 1146 - 1151
http://dx.doi.org/10.4161/hv.20923
Abstract | Full Text | PDF

This paper reviews and compares two autologous vaccine technologies for human melanoma that failed to obtain marketing approval after 10–15 y of clinical development—the HSP vaccine invented by Srivastava and developed by the company, Antigenics, and the hapten-modified cellular vaccine invented by Berd and developed by AVAX Technologies. Both vaccines had a strong basic science background with a well-understood mechanism of action. The HSP vaccine failed in a phase III pivotal trial, while the haptenized cellular vaccine was never adequately tested in a phase III trial because of regulatory and financial problems. It is proposed that the phase I-II clinical trials of the HSP vaccine neglected to define optimal dose, schedule, and route of administration, which, together with safety, are the major reasons for doing such trials. Therefore, the phase III trial was bound to fail because it was based on insufficient immunopharmacological information. Developers of the haptenized cellular vaccine underestimated the manufacturing and regulatory hurdles inherent to that technology and were therefore unable to complete a pivotal trial. Valuable lessons can be learned by acknowledging the mistakes made in these attempts to bring forward new treatments that could have eased the burdens of melanoma patients.

Open Access Article

Challenges in the development of an autologous heat shock protein based anti-tumor vaccine

Dirk J. Reitsma and Austin J. Combest
Pages 1152 - 1155
http://dx.doi.org/10.4161/hv.21382
Full Text | PDF

Immunotherapy with autologous tumor cell vaccines for treatment of occult disease in early stage colon cancer

Michael G. Hanna, Jr
Pages 1156 - 1160
http://dx.doi.org/10.4161/hv.20740
Abstract | Full Text | PDF

At the cellular level it is clear that cancer is a genetic disease arising as a clone that expands and grows in an unregulated manner. While it has always been presumed that neoplasia is a consequence of somatic cell mutations, only in the last few years has the magnitude and diversity of these mutations been elucidated by modern DNA sequencing technology. Immunotherapy is the premier biological approach to targeted therapy. Target therapies require targets. In this case the targets are tumor specific or associated antigens, the proteins expressed from these somatic cell mutations. While the immunotherapeutic approach to eliminating cancer was launched with the assumption that cancer cells were homogeneous, the recent genomic understanding of tumor cells indicates that there is both inter- and intra-tumoral heterogeneity. This presentation will discuss the consequences of this new knowledge of tumor cell biology to the immunotherapeutic approach to treating cancer.

SPECIAL FOCUS EDITOR'S CORNER

Open Access Article

Cancer vaccines: Are we there yet?

Michael G. Hanna, Jr.
Pages 1161 - 1165
http://dx.doi.org/10.4161/hv.21660
Abstract | Full Text | PDF

For nearly two decades there has been an abundance of research and clinical development programs underway to develop active specific immunotherapies, to educate the patient’s immune response, specifically the T-cell immunity and memory, to recognize and destroy tumor cells by cell-mediated cellular toxicity. While many of these technology platforms achieved promising results in preclinical and clinical phase I and II clinical trials, essentially all but one have failed to achieve FDA market approval as a therapeutic drug product.