Table of Contents

Volume 5, Issue 7

  July 2009

  Pages 435 - 506

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva Riedmann
Page 435
PDF




PORTRAIT OF A LEADING VACCINOLOGIST

Open Access Article

Working towards an HIV/AIDS vaccine

Harriet L. Robinson
Pages 436 - 438
PDF




BOOK REVIEW

Open Access Article

Influenza vaccines for the future

Susanna Esposito and Nicola Principi
Pages 439 - 440
Abstract | PDF

The book edited by Rino Rappuoli and Giuseppe Del Giudice reviews most of the problems related to the development of influenza vaccines and gives readers a complete panorama of all the most major advances that have been made over the last few years. The chapters have been written by various European, American and Australian experts in the field, and the references are up to date. All of the chapters are closely related and can be easily understood by readers without a previous detailed knowledge of infectious diseases and vaccinology. Finally, although most of the contributors work for a vaccine manufacturer, the available data are given without partisan judgements.




REVIEWS

Open Access Article

Sex differences in injection site reactions with human vaccines

Ian F. Cook
Pages 441 - 449
Abstract | PDF

Adverse events following immunization (AEFI) are not uncommon, with injection site reactions (ISRs) being the most common. 
Predictors of injection site reactions are vaccine factors (antigen characteristics, antigen dose, dose number of antigen, antigen adjuvanting and type of diluent), vaccine administration factors (site and route of administration) and vaccinee factors (age and sex, the latter the subject of this review).
1074 studies which reported ISRs were retrieved by searching of on line journals and databases.  Analysis of these data for sex-difference was only reported in 57 studies, with 54 of these studies reporting a sex-difference (42 in subjects > 17 years and 12 in subjects < 17 years).
In accord with the well documented greater pain sensitivity in females compared with males, in all studies with vaccines which reported pain during and post vaccination (hepatitis A, B, diphtheria/tetanus toxoid, diphtheria/tetanus/pertussis[DTaP and Tdap], anthrax and inactivated influenza), females reported a greater rate of pain than males.
The pathophysiology of the sex-difference in local reactions (induration, tenderness, erythema, pruritus) following vaccination is clearly multifactorial with hypersensitivity reaction (type III, Arthus reaction-antigen/antibody immune complex formation), route of administration and hormonal factors being suggested.
The data presented in this review demonstrate that studies of AEFI should recruit similar numbers of females and males and that these data should be analysed for sex-difference.  Additionally, unlike as at present, reporting of analysis of AEFI data by sex should become standard practice.

Open Access Article

Women and vaccinations: From smallpox to the future, a tribute to a partnership benefiting humanity for over 200 years

Sanjoy Datta, Neerja Bhatla, Margaret Burgess, Matti Lehtinen and Hans Bock
Pages 450 - 454
Abstract | PDF

Vaccines were first developed in England over 200 years ago and have made a significant positive impact on human society since. Not often realised is the intimate relationship shared between vaccines and women. Women were key to the initial development of vaccines; some were even advocating the concept of protection against infectious disease through prior asymptomatic infection (by variolation) before the publication of the report of the first successful smallpox vaccination in 1798.
Since that milestone, women have been important partners in the development of vaccines and advocates for their widespread introduction. Modern vaccine development would not be possible without the altruistic informed consent granted by many women for the participation of themselves or their children in vaccine clinical trials all over the world.
Vaccines have rewarded women handsomely in return. Individual women benefit in many ways ranging from safer pregnancies to preventing cancers to attractive, unblemished skin. Some vaccines are even specifically designed to prevent diseases primarily affecting women such as cervical cancer.
Vaccines also have offered societal benefits to women. These include better maternal health and fostering an environment more amenable to effective family planning. With these advances, women become more empowered and have access to better economic opportunities.
The challenge of meeting the millennium development goals specifically targeted for women will be facilitated by vaccines. A better realisation by women of the benefits of this partnership secured over the past 200 years will enable them to reap fully the rewards of the future.





RESEARCH PAPERS

Open Access Article

Safety of a refrigerator-stable varicella vaccine (VARIVAX®) in healthy 12- to 15-month-old children – a randomized, double-blind, cross-over study

Giuseppe Ferrera, Vincent Gajdos, Stéphane Thomas, Clément Tran and Anne Fiquet
Pages 455 - 460
Abstract | PDF

The safety of a single injection of the refrigerator-stable formulation of varicella vaccine VARIVAX® was assessed in a blind, randomized, cross-over trial. 507 healthy children aged 12 to 15 months received subcutaneous injections of VARIVAX on day 0 and the measles, mumps and rubella vaccine (M-M-R®II) on day 42 or M-M-R II on day 0 and VARIVAX on day 42. To maintain blinding, injections were given by a study nurse not involved in safety assessments. M-M-R II acted as a reference to validate the safety assessment, as its safety profile is well known in this age range. Parents or legal guardians recorded adverse events for 42 days following each injection. Solicited injection-site reactions (erythema, swelling, pain) were recorded on days 0 to 4. Other injection-site reactions, daily temperature, rashes and systemic adverse events were recorded on days 0 to 42, and serious adverse events until the final study visit. The safety profile of M-M-R II was consistent with previous reports. Following VARIVAX administration, 47.7% of children had at least one vaccine-related adverse event. Solicited injection-site reactions were reported in 13.0% of children, and 17.2% had at least one other injection-site reaction between days 0 and 42. Most reactions were small (≤2.5 cm) or of mild intensity. Pyrexia, reported in 25.3% of children, was the most common vaccine-related systemic adverse event. Varicella or varicella-like rashes were reported in 16 children (3.2%), of which seven cases were varicella-like rashes at the injection site. In summary, the refrigerator-stable formulation of VARIVAX had a good safety profile and was well tolerated in healthy children aged 12 to 15 months, consistent with experience with the frozen formulation of VARIVAX.
ClinicalTrials.gov identifier: NCT00432731.


Open Access Article

A fluorescence-based opsonophagocytosis assay to measure the functional activity of antibody to group B Streptococcus

Hilde-Kari Guttormsen, Samantha J. Mascuch, Julia C. West and Lawrence C. Paoletti
Pages 461 - 466
Abstract | PDF

An in vitro assay designed to measure the functional activity of vaccine-induced antibody is a necessary component of any vaccine development program.  Because traditional efficacy studies of vaccines to prevent neonatal diseases caused by group B Streptococcus (GBS) are unlikely given the effectiveness of current antibiotics and screen-based surveillance practices, the ability to efficiently and effectively measure functional antibody responses may be of particular importance.  GBS, like other encapsulated bacterial pathogens, are susceptible to opsonization by specific antibody and complement and subsequent killing by the host’s effector cells.  The in vitro opsonophagocytosis and killing assay (OPA) mimics this in vivo defense strategy and has been used for decades to measure the functionality of natural and/or vaccine-induced GBS-specific antibody.  Here we describe a fluorescence-based OPA (flOPA) that measures the ability of specific antibody to opsonize fixed, fluorescently labeled GBS or antigen-coated fluorescent microspheres for uptake by differentiated HL-60 cells in the presence of complement.  Compared to the classical OPA, the flOPA is standardized with respect to effector cells, complement, and antigenic targets.  The GBS flOPA is also less time-intensive and has the potential to measure antibody to multiple antigens simultaneously.  Quantitative functional antibody determinations using the flOPA may serve as a surrogate measure of GBS vaccine effectiveness in lieu of traditional phase 3 efficacy trials.

Open Access Article

Cervarix™, the GSK HPV-16/HPV-18 AS04-adjuvanted cervical cancer vaccine, demonstrates stability upon long-term storage and under simulated cold chain break conditions

David Le Tallec, Diane Doucet, Abdelatif Elouahabi, Pol Harvengt, Michel Deschuyteneer and Marguerite Deschamps
Pages 467 - 474
Abstract | PDF

Cervarix™ is a recombinant human papillomavirus (HPV)-16 and -18 L1 virus-like-particle (VLP) AS04-adjuvanted vaccine designed to protect against cervical intraepithelial neoplasia and cervical cancer caused by the HPV types 16 and 18. Assessment of the stability of the vaccine during long-term storage and after transient exposure to temperatures out of normal storage range is an integrated part of vaccine quality evaluation. This assessment was done with vaccine samples stored at 2-8°C for up to 36 months, with or without simulated cold chain break (either one week at 37°C, or two or four weeks at 25°C). Among the stability-indicating parameters, antigenicity and immunogenicity were evaluated along with L1 antigen integrity and adsorption to aluminum. Differential scanning calorimetry (DSC) was used to investigate the structural stability of the VLPs before and after vaccine formulation and over time. Cervarix™ was stable at 2-8°C for at least 3 years, and the occurrence of cold chain break had no impact, as shown by unchanged product characteristics during the full storage period. DSC analysis demonstrated that the structure of the HPV-16 and -18 L1 proteins and their corresponding VLPs was not affected throughout the manufacturing process. Moreover, the structure of aluminum-adsorbed HPV-16 and -18 L1 VLPs was robust over a 14-month test period. In conclusion, Cervarix™ was very stable upon long-term storage at 2-8°C with or without transient exposure to higher temperatures (up to 37°C). The observed robust structure of the L1 VLPs contributes to the excellent stability of Cervarix™.

Open Access Article

The candidate tuberculosis vaccine Mtb72F/AS02A: Tolerability and immunogenicity in humans

Kenneth Von Eschen, Royce Morrison, Madeleine Braun, Opokua Ofori-Anyinam, Els De Kock, Priya Pavithran, Marguerite Koutsoukos, Philippe Moris, Daniel Cain, Marie-Claude Dubois, Joe Cohen and W. Ripley Ballou
Pages 475 - 482
Abstract | PDF

Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFN γ in the ELISPOT assay and CD4+T cells expressing at least 2 activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an, acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.

Open Access Article

Safety and immunogenicity of an indigenously developed Haemophilus influenzae type b conjugate vaccine through various phases of clinical trials

Hitt J. Sharma, Amrik S. Multani, Ashok K. Dutta, Surekha M. Joshi, Sushma Malik, Subodh Bhardwaj, Anita Chakravarty, Gajanan S. Namjoshi, Sameer Parekh and Vikas Verma
Pages 483 - 487
Abstract | PDF

In view of the need for a cost effective Haemophilus influenzae type b (Hib) conjugate vaccine, a lyophilized vaccine as capsular polysaccharide (PRP) conjugated to tetanus toxoid (Sii HibPRO) was indigenously developed by Serum Institute of India Ltd, Pune (SIIL).  During 2004-07, this new vaccine underwent a series of clinical studies before its licensure by, National Regulatory Authority (NRA). This paper discusses the results obtained during the clinical development of this vaccine.  On finding the vaccine to be safe in animal toxicity studies, a Phase I single dose study was carried out to assess the safety profile of Sii HibPRO in healthy adult male volunteers. Subsequently, in Phase III pre-licensure study, immunogenicity and safety of Sii HibPRO was assessed and compared with Hib tetanus conjugate vaccine (Act-HIB) of Aventis, France. Immunogenicity was evaluated based upon serum anti-PRP IgG antibody concentrations by ELISA at prevaccination and one month each after the second and third dose. Safety was evaluated by recording details of adverse events after each dose of the vaccine.  Postvaccination after the third dose, there was 100% seroprotection (anti PRP IgG titre ≥0.15 µg/ml) in both the groups. Long term protection (≥1µg/ml) was achieved in 95.2% and 98.06% infants in Sii HibPRO and Act-HIB groups, respectively.  At 15 months, prior to booster dose, 30 children in each group were evaluated and all were found to be seroprotected. Post booster, all of them responded with a strong boost response. Safety of Sii HibPRO was re-established in the post marketing surveillance in which 2739 doses were administered to 1029 infants, in 23 cities across India.




COMMENTARIES

Open Access Article

The green vaccine: A global strategy to combat infectious and autoimmune diseases

Abdoreza Davoodi-Semiromi, Nalapalli Samson and Henry Daniell
Pages 488 - 493
Abstract | PDF

Plant derived oral green vaccines eliminate expenses associated with fermenters, purification, cold storage/transportation and sterile delivery. Green vaccines are expressed via the plant nuclear or chloroplast genomes.  Chloroplast expression has advantages of hyper-expression of therapeutic proteins (10,000 copies of transgene per cell), efficient oral delivery and transgene containment via maternal inheritance.   To date, 23 vaccine antigens against 16 different bacterial, viral or protozoan pathogens have been expressed in chloroplasts. Mice subcutaneously immunized with the chloroplast derived anthrax protective antigen conferred 100% protection against lethal doses of the anthrax toxin. Oral immunization (ORV) of F1-V antigens without adjuvant conferred greater protection (88%) against 50-fold lethal dose of aerosolized plague (Yersinia pestis) than subcutaneous (SQV) immunization (33%). Oral immunization of malarial vaccine antigens fused to the cholera antigen (CTB-AMA1/CTB-Msp1) conferred prolonged immunity (50% life span), 100% protection against cholera toxin challenge and inhibited proliferation of the malarial parasite. Protection was correlated with antigen-specific titers of intestinal, serum IgA & IgG1 in ORV and only IgG1 in SQV mice, but no other immunoglobulin. High level expression in edible plant chloroplasts ideal for oral delivery and long-term immunity observed should facilitate development of low cost human vaccines for large populations, at times of outbreak.

Open Access Article

Mumps outbreaks in highly vaccinated populations: What makes good even better?

Corinne Vandermeulen, Geert Leroux-Roels and Karel Hoppenbrouwers
Pages 494 - 496
Abstract | PDF

In 2006 an outbreak of mumps occurred in the US and amazingly the majority of cases were individuals that had received two vaccine doses. This unexpected outbreak may be due to the low immunogenicity of the mumps vaccine, insufficient vaccination coverage or a combination of both. Both humoral and cellular immune responses induced by the mumps vaccine are considered to contribute to the vaccine-induced protection. The magnitude and persistence of these responses determine the overall efficacy of the vaccine and ultimately the degree of vaccination coverage that needs to be reached to eliminate the mumps virus. Although Finland and the US have used the same mumps vaccine for decades, a mumps outbreak has been reported in the US while in Finland this virus appears to be eliminated. In this commentary we speculate on the factors that may be responsible for this striking difference.


Open Access Article

Improving pertussis vaccination

Guy A.M. Berbers, Sabine C. de Greeff and Frits R. Mooi
Pages 497 - 503
Abstract | PDF

Despite a high vaccine coverage, pertussis has re-emerged and has become the most prevalent vaccine preventable disease in developed countries. The re-emergence of pertussis has been attributed to various factors, including increased awareness, improved diagnostics, suboptimal vaccines, waning vaccine-induced immunity and pathogen adaptation. Waning immunity in combination with pathogen adaptation are probably the main factors which contribute to the continued circulation of B. pertussis strains. The switch from whole cell vaccines (Pw) to acellular vaccines (Pa) has been successful in reducing side-effects and restoring the public confidence in pertussis immunizations. It has also facilitated the introduction of booster vaccinations at later ages with favorable effects. However, there is still significant circulation of B. pertussis among adolescents and adults who are a major source of infection of infants to young to be (fully) vaccinated. In the short term, the introduction of cocooning vaccination is the most (cost-)effective way to reduce the pertussis burden in infants. In the long term, improved pertussis vaccines should be developed which induce long lasting immunity.