Abstract
The 11th Annual Conference on Vaccine Research, hosted by the National Foundation for Infectious Disease, attracted approximately 450 leaders in the fields of epidemiology, health economics, immunology and vaccinology, making it the largest scientific meeting devoted exclusively to vaccine research and technology. The conference highlighted recent advancements in vaccine design, including the discovery of new adjuvants, cytokines and regulatory pathways. Other topics included a comprehensive overview of the development and uses of cutaneous vaccination and a discussion of recently licensed vaccines against the human papillomavirus, herpes zoster virus, meningococcal disease and rotavirus and a discussion on the importance of redesigning and increasing the coverage of the influenza vaccine. Keynote remarks were provided by the demographer and economist David E Bloom (Harvard School of Public Health, USA), who argued that traditional economic evaluations of vaccine interventions have failed to account for the full range of benefits that can accrue from vaccination. These benefits are substantial in size and potentially decisive with respect to the bottom-line results of benefit–cost calculations.
Enhancing immunogenicity
Adjuvants have been used since the early 20th Century to enhance the immunogenicity of vaccines. At one time, early adjuvants included common pantry items, such as breadcrumbs, starch oil and tapioca. A new generation of more sophisticated adjuvants that are useful in eliciting strong cellular immune responses has recently come to the fore. These new adjuvants include specific nucleotide sequences of bacterial DNA, such as CpG oligodeoxynucleotides (ODN) and oil-in-water emulsions containing saponin.
Dennis Klinman (US NIH, MD, USA) discussed the use of CpG ODN as an adjuvant for the anthrax vaccine absorbed (AVA). His results show that CpG ODN enhances the vaccine’s immunogenicity by improving the rapidity, magnitude, duration and affinity of the protective response induced by AVA in humans, mice and rhesus macaques. Risini Weeratna (Coley Pharmaceuticals, ON, Canada) also discussed the role of CpG as an adjuvant and showed that CpG improved antibody and T-cell responses – including more rapid seroconversion and pr-otection, and stronger and longer-lasting responses – in 37 vaccine clinical trials. Debbie Drane (CSL, Victoria, Australia) discussed a series of saponin-based adjuvants, including ISCOMATRIX®, a complex of crude quillaia, cholesterol and phospholipids. In 13 clinical studies, ISCOMATRIX was shown to enhance and accelerate antibody and T-cell (CD4 and CD8) immune responses.
Ennio De Gregorio (Novartis, Italy) used microanalysis techniques to study the pathways through which adjuvants work. He injected the quadriceps of mice with either MF59 (Chiron) or CpG and alum, and performed a microanalysis of the muscle tissue. His data show that each adjuvant elicited cytokine/cytokine receptor responses, prostaglandin synthesis and regulation, IL-1 signaling and matrix metalloproteinase activity. MF59 was the more potent activator of the mouse transcriptome at the injection site and induced the expression of a large number of chemoattractants (CC-chemokine ligands and CXC chemokine ligands). MF59 was also the more potent activator of the genes involved in leukocyte transendothelial migration.
Cutaneous vaccination & its global implications
Bruce Weniger (CDC, GA, USA) defined cutaneous vaccination as a vaccine delivery method that targets any part of the skin, which is essentially one large immune organ that protects the body from environmental assault. Its unique properties have become the subject of recent vaccine research.
Tanja de Gruijl (Vrije Universiteit Medical Center, Amsterdam, The Netherlands) developed a human skin explant model to demonstrate the role and importance of two types of skin-dwelling dendritic cells (DCs) – Langerhans’ cells and dermal DCs – in eliciting an immune response. Her model shows that both cell types can drain antigen from the skin to the lymph nodes, where they can effectively prime T- and/or B-cell-mediated responses. The stratum corneum (SC), the outermost 15–20-µm-thick layer of skin, is a formidable barrier that cutaneous vaccines must penetrate in order to access the Langerhans’ cells and dermal DCs. Samir Mitragoni (University of California, Santa Barbara, CA, USA) discussed several techniques for breaching the SC, including iontophoresis and electroporation, both of which increase the permeability of the skin to vaccines. Another cutaneous method uses a high-velocity injector to deliver DNA-coated gold nanoparticles across the SC.
Cutaneous vaccination is a particularly appealing method for use in the developing world because it obviates the need for training in subcutaneous delivery methods and the incineration of biohazardous waste. As Martin Friede (WHO, Geneva, Switzerland) noted, however, there are several challenges to extending these cutaneous techniques to the developing world; he gave particular attention to the compatibility issues that may arise during the transition from a standard needle-and-vial approach to the use of more heterogeneous vaccine formulations and applicators. Friede cautioned manufacturers of these vaccine-delivery technologies to consider how skin age, hydration and UV exposure might affect the breaching of the SC, especially when considering a global consumer base.
Newly licensed prophylactic vaccines
The vaccine market is rapidly expanding and its target populations are continuously evolving. Vaccines are no longer for children alone; rather, they are being designed for people of all ages, and with great attention being paid to the unique health concerns of different target age groups.
There are more than 100 strains of the human papillomavirus (HPV), 37 of which are genital (mucosal) types that might lead to cervical cancer. Laura Koutsky (University of Washington, DC, USA) discussed the clinical trial outcomes of two recently licensed vaccines against HPV: GlaxoSmithKline’s bivalent Cervarix® and Merck’s quadrivalent Gardasil®. Among women aged 15–26 years without prior type-specific infection, Gardasil and Cervarix were 95 and 90% efficacious, respectively, in preventing HPV16/18 cervical lesions. The quadrivalent Gardasil, which offers additional protection against HPV6/11, was 96% ef-ficacious in preventing HPV6/11/16/18.
The varicella zoster virus is the cause of herpes zoster (HZ), commonly known as shingles, a disease that is most prevalent among the age group of 60 years or older. Michael Oxman (University of California, CA, USA) discussed the results of a double-blind, placebo-controlled trial of the newly licensed vaccine against HZ, Merck’s Zostavax™. The study involved 38,546 subjects 60 years of age or older; this group was stratified according to age (60–69 and ≥3;70 years) and individuals in each group were randomized to receive either a single dose of Zostavax or placebo. Results show that the vaccine was 65.7% efficacious for the prevention of postherpetic neuralgia, a common and painful consequence of HZ, among 60–69-year olds, and was 66.8% efficacious among subjects 70 years of age and older.
A total of one in four cases of meningococcal disease, a major cause of bacterial meningitis and sepsis worldwide, results in long-term disability or death. Nancy Messonnier (CDC, USA) discussed a clinical trial of two vaccines against meningococcal disease for children aged 2–10 years – the tetravalent meninogococcal vaccine (MCV4), Menactra®, and the tetravalent meningococcal polysaccharide vaccine (MPSV4), Menomune®. Each vaccine targets serotypes A, C, Y and W-135, which, taken together, account for the majority of meningococcal disease among adolescents. Results of the double-blind study showed that, on average, subjects who received Menactra demonstrated greater seroconversion for each of the four serogroups covered by the vaccine than those who received Menomune.
Rotavirus is responsible for nearly 800,000 child deaths each year, most of which occur in the developing world. Roger Glass (Fogarty Institute, CA, USA) discussed the possible challenges associated with extending coverage of two newly licensed oral vaccines against rotavirus – GlaxoSmithKline’s Rotarix® and Merck’s RotaTeq® – to the developing world, where oral vaccines have historically yielded a lower level of protection among children. Early results of Rotarix effectiveness trials are worrisome: only 44% of children in South Africa and 55% of children in Bangladesh have shown an immune response to the vaccine. According to Glass, there is something unique about the GI tracts of these children that impedes their immune response to oral vaccines.
Implications of vaccination against influenza
The current US immunization schedule recommends that all children 0–59 months of age should be vaccinated against influenza. By the 2009–2010 influenza season, the Advisory Committee on Immunization Practices (ACIP) is expected to recommend an extension of coverage of the influenza vaccine to all 5–18-year olds as well.
According to Matt Daley (University of Colorado, CO, USA), extending coverage of the influenza vaccine will place great strain on the primary-care system, which will have to accommodate millions of additional doctors’ visits needed to administer the vaccine during the influenza season. However, as James King (University of Maryland, MD, USA) noted, the benefits of the influenza vaccination will be conferred not only to the vaccinated members of a community but also to those who are unvaccinated. In a series of experiments in which primary-school-aged children in select Maryland counties were vaccinated against influenza, a reduction in influenza-related school absences was seen throughout the treatment counties at both primary- and high-school levels. These results support the claim that children are amplifiers of the influenza virus and underscore the communal benefits of va-ccinating school children against influenza.
Current influenza vaccines are sensitive to the continuous alteration of the distal regions of hemagglutinin A; this variability necessitates the development of seasonal vaccines against influenza. Hildegund Ertl (Wistar Institute, PA, USA) discussed the design of a new vaccine against influenza that would target a more conserved region of the virus. The design would also involve incorporating the conserved region into E1-deleted adenoviral vectors, which have been shown to induce sustained gene product-specific T-cell responses, in particular, CD8+ T cells. An influenza vaccine that combines the targeting of a more conserved region of the virus with a sustained T-cell response may obviate the need for a yearly vaccine against varying seasonal strains and could, potentially, mitigate the stress imposed on the primary care system.
Summary
The advent of highly immunogenic adjuvants and skintargeted vaccination technologies will further the achievement of global immunization against a range of pathogens. The combination of these two innovations might also encourage dose-sparing, since smaller amounts of vaccine would be required to induce the same or a stronger immune response; this outcome is ideal for scarce and/or expensive vaccines. The development of recent vaccines against HPV, HZ, meningococcal disease and rotavirus will unequivocally bring about greater reductions in related morbidity and mortality; more importantly, these vaccines demonstrate that children are no longer the only ones benefiting from vaccine technologies. Finally, the design of a new influenza vaccine that targets a more conserved portion of the influenza virus, and whose effect would be long lasting, could, potentially, mitigate the anticipated strain on vaccine supply and administration that the ACIP extension of the influenza vaccine might engender in the USA.
Financial & competing interest disclosure
The author has no relevant involvement with any organizations or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership to options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production on this manuscript.