Efficacy of the herpes zoster zubunit vaccine in adults 70 years of age or older

Background: A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70).

Methods: This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.

Results: In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups.

Conclusions: In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older.

The effect of plant tissue and vaccine formulation on the oral immunogenicity of a model plant-made antigen in sheep

Antigen-specific antibody responses against a model antigen (the B subunit of the heat labile toxin of enterotoxigenic Escherichia coli, LTB) were studied in sheep following oral immunisation with plant-made and delivered vaccines. Delivery from a root-based vehicle resulted in antigen-specific immune responses in mucosal secretions of the abomasum and small intestine and mesenteric lymph nodes. Immune responses from the corresponding leaf-based vaccine were more robust and included stimulation of antigen-specific antibodies in mucosal secretions of the abomasum. These findings suggest that oral delivery of a plant bioencapsulated antigen can survive passage through the rumen to elicit mucosal and systemic immune responses in sheep. Moreover, the plant tissue used as the vaccine delivery vehicle affects the magnitude of these responses.

Use of the wound-inducible NtQPT2 promoter from Nicotiana tabacum for production of a plant-made vaccine

The wound-inducible quinolinate phosphoribosyl transferase promoter from Nicotiana tabacum (NtQPT2) was assessed for its capacity to produce B-subunit of the heat-labile toxin (LTB) from enterotoxigenic Escherichia coli in transgenic plant tissues. Comparisons were made with the widely used and constitutive Cauliflower Mosaic Virus 35S (CaMV35S) promoter. The NtQPT2 promoter produced somewhat lower average concentrations of LTB protein per unit weight of hairy root tissue but allowed better growth thereby producing similar or higher overall average yields of LTB per culture batch. Transgenic tobacco plants containing the NtQPT2-LTB construct contained LTB protein in roots but not leaves. Moreover, wounding NtQPT2-LTB transgenic plants, by removal of apices, resulted in an approximate 500% increase in LTB levels in roots when analysed several days later. CaMV35S-LTB transgenic plants contained LTB protein in leaves and roots but wounding made no difference to their LTB content.

Evidence for a common role for the serine-type Plasmodium falciparum serine repeat antigen proteases : implications for vaccine and drug design

Serine repeat antigens (SERAs) are a family of secreted “cysteine-like” proteases of Plasmodium parasites. Several SERAs possess an atypical active-site serine residue in place of the canonical cysteine. The human malaria parasite Plasmodium falciparum possesses six “serine-type” (SERA1 to SERA5 and SERA9) and three “cysteine-type” (SERA6 to SERA8) SERAs. Here, we investigate the importance of the serine-type SERAs to blood-stage parasite development and examine the extent of functional redundancy among this group. We attempted to knock out the four P. falciparum serine-type SERA genes that have not been disrupted previously. SERA1, SERA4, and SERA9 knockout lines were generated, while only SERA5, the most strongly expressed member of the SERA family, remained refractory to genetic deletion. Interestingly, we discovered that while SERA4-null parasites completed the blood-stage cycle normally, they exhibited a twofold increase in the level of SERA5 mRNA. The inability to disrupt SERA5 and the apparent compensatory increase in SERA5 expression in response to the deletion of SERA4 provides evidence for an important blood-stage function for the serine-type SERAs and supports the notion of functional redundancy among this group. Such redundancy is consistent with our phylogenetic analysis, which reveals a monophyletic grouping of the serine-type SERAs across the genus Plasmodium and a predominance of postspeciation expansion. While SERA5 is to some extent further validated as a target for vaccine and drug development, our data suggest that the expression level of other serine-type SERAs is the only barrier to escape from anti-SERA5-specific interventions.

Bypassing luminal barriers, delivery to a gut addressin by parenteral targeting elicits local IgA responses

Induction of mucosal immunity, particularly to subunit vaccines, has been problematic. The primary hurdle to successful mucosal vaccination is the effective delivery of vaccine antigen to the mucosal associated lymphoid tissue. Physical and chemical barriers restrict antigen access and, moreover, immune responses induced in the mucosa can be biased towards tolerance or non-reactivity. We proposed that these difficulties could be circumvented by targeting antigen to the gastrointestinal associated lymphoid tissue via systemic (parenteral) rather than alimentary routes, using antibodies specific for the mucosal addressin cellular adhesion molecule-1 (MAdCAM). After intravenous or intramuscular injection of such rat antibodies in mice, we found a greatly enhanced (up to 3 logs) anti-rat antibody response. MAdCAM targeting induces a rapid IgA antibody response in the gut and vastly improves the systemic antibody response. Targeting also enhanced T cell proliferation and cytokine responses. Parenteral targeting of mucosal addressins may represent a generic technique for bypassing mucosal barriers and eliminating the need for adjuvants in the induction of proximal and systemic immunity.

The cost of seasonal respiratory illnesses in Australian children: the dominance of patient and family costs and implications for vaccine use

Respiratory viral infections are one of the next group of diseases likely to be targeted for prevention in childhood by the use of vaccines. To begin collecting necessary epidemiology and cost information about the illnesses caused by these viruses, we conducted a prospective cohort study in 118 Melbourne children between 12 and 71 months of age during winter and spring 2001. We were interested in calculating an average cost per episode of community-managed acute respiratory disease, in identifying the key cost drivers of such illness, and to identify the proportion of costs borne by the patient and family. There were 202 community-managed influenza-like illnesses identified between July and December 2001, generating 89 general practitioner visits, and 42 antibiotic prescriptions. The average cost of community-managed episodes (without hospitalisation) was $241 (95% CI $191 to $291), with the key cost drivers being carer time away from usual activities caring for the ill child (70% of costs), use of non-prescription medications (5.4%), and general practice visits (5.0%). The patient and family met 87per cent of total costs. The lowest average cost occurred in households from the highest income bracket. Acute respiratory illness managed in the community is common, with the responsibility for meeting the cost of episodes predominantly borne by the patient and family in the form of lost productivity. These findings have implications for preventive strategies in children, such as the individual use of, or implementation of public programs using, currently available vaccines against influenza and vaccines under development against other viral respiratory pathogens.

Bacille Calmette-Guérin vaccine-related disease in HIV-infected children: a systematic review

Objective: To describe the characteristics and risk of bacille Calmette-Guérin (BCG) vaccine related disease in human immunodeficiency virus (HIV) infected infants.
Methods: Systematic literature review of articles published from 1950 to April 2009 in the English language. We identified all microbiologically confirmed cases of disseminated BCG disease in vertically HIV-infected children reported in the literature.
Results: Sixteen observational studies and 11 case reports/series were included. Observational studies suffered from high rates of loss to follow-up and death. Loco-regional BCG disease was reported in both HIV-infected and non-infected children. Disseminated BCG disease was reported only in children with immunodeficiency and only in studies employing sophisticated laboratory techniques. Sixty-nine cases of disseminated BCG were identified in the literature: 47 cases were reported in six observational studies, the majority (41/47) from the Western Cape of South Africa. A Brazilian cohort study reported no cases of disseminated BCG amongst 66 HIV-infected children observed over a 7-year period. A recent South African surveillance study reported 32 cases of disseminated BCG over a 3-year period, estimating the risk of disseminated BCG to be 992 per 100 000 vaccinations in HIV-infected children. Few cases of severe disseminated TB were reported in the cohort studies among HIV-infected children vaccinated with BCG.
Conclusion: Data on the risk of BCG vaccination in HIV-infected children are limited. Targeted surveillance for BCG complications employing sophisticated diagnostic techniques is required to inform vaccination policy.

HIV-1 vaccine development : tackling virus diversity with a multi-envelope cocktail

A major obstacle to the design of a global HIV-1 vaccine is viral diversity. At present, data suggest that a vaccine comprising a single antigen will fail to generate broadly reactive B-cell and T-cell responses able to confer protection against the diverse isolates of HIV-1. While some B-cell and T-cell epitopes lie within the more conserved regions of HIV-1 proteins, many are localized to variable regions and differ from one virus to the next. Neutralizing B-cell responses may vary toward viruses with different i) antibody contact residues and/or ii) protein conformations while T-cell responses may vary toward viruses with different (i) T-cell receptor contact residues and/or (ii) amino acid sequences pertinent to antigen processing. Here we review previous and current strategies for HIV-1 vaccine development. We focus on studies at St. Jude Children's Research Hospital (SJCRH) dedicated to the development of an HIV-1 vaccine cocktail strategy. The SJCRH multi-vectored, multi-envelope vaccine has now been shown to elicit HIV-1-specific B- and T-cell functions with a diversity and durability that may be required to prevent HIV-1 infections in humans.

HIV vaccine rationale, design and testing

A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic diversity has been addressed by vaccine design. For example, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax® presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific Bcell and T-cell responses, are reviewed.

Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV

A central obstacle to the design of a global HIV-1 vaccine is virus diversity. Pathogen diversity is not unique to HIV-1, and has been successfully conquered in other fields by the creation of vaccine cocktails. Here we describe the testing of an HIV-1 envelope cocktail vaccine. Six macaques received the vaccine, delivered by successive immunizations with recombinant DNA, recombinant vaccinia virus and recombinant envelope proteins. Following vaccination, animals developed a diversity of anti-envelope antibody binding and neutralizing activities toward proteins and viruses that were not represented by sequence in the vaccine. T-cells were also elicited, as measured by gamma-interferon production assays with envelope-derived peptide pools. Vaccinated and control animals were then challenged with the heterologous pathogenic SHIV, 89.6P. Vaccinated monkeys experienced significantly lower virus titers and better maintenance of CD4+ T-cells than unvaccinated controls. The B- and T-cell immune responses were far superior post-challenge in the vaccinated group. Four of six vaccinated animals and only one of six control animals survived a 44-week observation period post-challenge. The present report is the first to describe pathogenic SHIV disease control mediated by a heterologous HIV-1 vaccine, devoid of 89.6 or SIV derivatives.

Overcoming diversity with a multi-envelope HIV vaccine

A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic diversity has been addressed by vaccine design: for example, the poliovirus vaccine includes 3 serotypes of poliovirus, and Pneumovax® presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific B-cell and T-cell responses, are reviewed.

A multi-vector, multi-envelope HIV-1 vaccine

The St. Jude Children's Research Hospital (St. Jude) HIV-1 vaccine program is based on the observation that multiple, antigenically distinct HIV-1 envelope protein structures are capable of mediating HIV-1 infection. A cocktail vaccine comprising representatives of these diverse structures (immunotypes) is therefore considered necessary to elicit lymphocyte populations that prevent HIV-1 infection. This strategy is reminiscent of that used to design a currently licensed and successful 23-valent pneumococcus vaccine. Three recombinant vector systems are used for the delivery of envelope cocktails (DNA, vaccinia virus, and purified protein) and each of these has been tested individually in phase I safety trials. A fourth clinical trial, in which diverse envelopes and vectors are combined in a prime-boost vaccination regimen, has been FDA-approved and is expected to commence in 2007. This trial will continue to test the hypothesis that a multivector, multi-envelope vaccine can elicit diverse 8- and T-cell populations that can prevent HIV-1 infections in humans.

Knowledge of human papillomavirus (HPV) and the HPV vaccine in a national sample of Australian men and women

Background: Human papillomavirus (HPV) knowledge has rarely been investigated in the context of a national vaccination program. The present study investigated HPV knowledge after the introduction of a national HPV vaccination program in Australia using a national sample of men and women. Methods: Questions assessing HPV knowledge were part of a broader national study of health and relationships administered via a computer-assisted telephone interview. These findings are from wave four of the study, conducted between 2007 and 2008. Knowledge questions about HPV included its association with cervical cancer, genital warts and abnormal Pap tests. Results: A total of 2634 women and 2556 men between the ages of 18 and 70 were interviewed. Overall, 62.8% (95% confidence interval (CI): 60.8–64.7%) of women and 38.3% (95% CI: 36.3–40.4%) of men had heard of HPV. Of these, 66.0% (95% CI: 64.1–67.9%) correctly answered that HPV is associated with cervical cancer, 50.2% (95% CI: 48.2–52.1%) answered that HPV is associated with abnormal Pap tests and 44.5% (95% CI:42.5–46.5%) answered that HPV causes warts. Predictors of good knowledge included being female, aged between 26 and 45, holding higher education levels and older age at first sex. Ever having a Pap test was also associated with awareness about HPV. Conclusion: One of the highest levels of knowledge about HPV in Australia to date is reported in the present study. Knowledge about the association between HPV and cervical cancer was particularly high, especially when compared with knowledge of the association with genital warts. This appears to be a consequence of the marketing of the HPV vaccine as a vaccination against cervical cancer.