Vaccines in clinical trials: infectious disease

As guest editors for this issue of Expert Review of Vaccines it has been a pleasure to collect into this edition a series of papers that reflect the international endeavor to prevent and cure the continuing burden of infectious disease. The focus of this special issue is on vaccines in clinical trials.

The last 50 years has seen a fantastic acceleration in the development, testing and implementation of life-saving vaccines that are now given routinely in clinical practice and in childhood in particular. Each of these vaccines came with a story to tell – pathogen discovery, antigen identification, laboratory development, assessment of safety, immunogenicity and efficacy, and ultimately a political drive to deliver vaccines and protect the populous. There is a tendency to think that the vaccines in early clinical studies today are the ‘difficult ones’ – that things that went before were relatively easy. In fact, many of the older vaccines faced enormous obstacles within their time that were eventually overcome. And whilst it is true that some of the pathogens reflected in this issue present particular challenges for vaccine developers with regard to immune evasion or genetic diversity, the molecular and immunological tools at our disposal today are unprecedented. As such, we feel that vaccine development in the coming decade can and should be tackled with optimism.

The articles presented in this issue make fascinating reading as they lay out the current status of the science of vaccinology. The clinical trial frequently reflects ‘judgment day’ for decades of laboratory work that has gone before, and as a result lines of investigation may reach an abrupt halt, drive studies back to the laboratory, or move forward rapidly into large clinical trials attracting funding and impetus. Either way, the successes and failures in clinical trials make an invaluable contribution to our understanding of disease pathogenesis and definitions of protective immunity.

Along with the scientific excitement of working with clinical trials, comes an enormous burden of bureaucracy to fit in with the regulatory requirements of our day with the ultimate aim of making clinical vaccine trials safe for today’s participants. A single data slide represents a whole team of investigators, their dogged commitment, and regulatory committees assembled to ensure safety and scientific rigor. This part of clinical trial work is rarely described and poorly appreciated by others in the scientific community. As such, we would like to take the opportunity to acknowledge this work here.

This story of how vaccine development has contributed to our understanding of disease pathogenesis and protective immunity, and of how modern molecular genetics is moving the field forward is perfectly represented in the manuscript by Anderson et al.[1] entitled ‘New frontiers in meningococcal vaccines’. In the 1960s, the first successful meningococcal (Mn) vaccines were based on T-cell-independent capsular polysaccharide antigens. The antibody generated by these vaccines was found to be short lived and so the immunological concept that B-cell memory maintenance required T-cell help further evolved. The development of protein–polysaccharide conjugate vaccines overcame this problem leading to a successful serogroup C Mn vaccine program in the UK in 1999. The quest to develop a universal vaccine for serogroup B Neisseria meningitidis remains to be completed as detailed in the article by Su and Snape [2]. This pathogen poses particular difficulties since the polysaccharide is a self-antigen rendering the host immuno-tolerant. But scientific excellence is evolving from this challenge and novel molecular approaches have been adopted that will ultimately be transferable to others in the vaccine field. Here, new candidate vaccine antigens have been identified, initially through the mining of the bacterial genome using a computer-based predictive program to identify putative antigens. These antigens have since been shown to play key roles in disease pathogenesis and some were identified as possible vaccine immunogens.

Despite the success of the Mn conjugate protein–polysaccharide vaccine, clinical studies have shown that immunogenicity in children, the population who are most susceptible to infection, needs to be improved as antibodies generated by immunization in early childhood are not sustained. We tackle this issue with a discussion of age-dependent B-cell immunity (article by Blanchard-Rohner and Pollard [3]) and suggest ways in which sustained protection might be achieved. Another important pathogen in children, particularly newborn infants is group B streptococcus. The vaccination of pregnant women to reduce bacterial colonization of the genital tract and prevent disease transmission to infants clearly brings complex challenges in terms of both regulation and the assessment of efficacy, which is elegantly described by Heath [4].

The eradication of polio from major parts of the globe represents the ultimate achievement through vaccination at a population level. Live-attenuated oral poliomyelitis vaccine that is cheap, easy to administer and efficacious has played a major role in this endeavor. However, this vaccine has been associated with vaccine-associated disease. By the end of 2013, it is hoped that the transmission of wild poliovirus will cease. At this point, new vaccine strategies based on nonvirulent polio strains will be needed to decrease the risk of the re-emergence of wild and vaccine-derived poliovirus outbreaks. The article by Verdijk et al.[5] clearly describes the current strategies to develop affordable inactivated poliovirus vaccines that may be widely employed once polio eradication is fully achieved.

Staphylococcus aureus infection is the scourge of hospital medicine, though with widespread antibiotic usage community-acquired disease is also on the increase. This complex pathogen with over 50 virulence factors coexists harmlessly on the skin and mucosal surfaces in 30–50% of healthy adults. Yet, the consequence of a break in host defenses is the development of severe disease. The bacterial virulence factors are currently the focus for novel vaccines described in the article by Anderson et al.[6] but the authors describe major gaps in our current understanding of why some people and not others develop invasive disease. A major challenge here will be the assessment of vaccine efficacy in a disease with so many diverse clinical manifestations.

Then there is malaria. This pathogen continues to wreak devastation worldwide with approximately a million deaths annually. Recent years have seen the rapid progress of both viral-vectored approaches and the use of RTS,S in clinical studies of efficacy. The article by Regules et al.[7] is a focused review on the development of RTS,S that clearly describes how vaccine strategies may benefit from the parallel development of appropriate adjuvants. We particularly liked the authors concluding sentence, “More so than ever, the future is bright and perseverance is the key”.

The particular challenges in the development of a vaccine that targets a highly genetically diverse pathogen is represented in the clinical studies on hepatitis C virus infection. The focus of the authors (Barnes et al.[8]) is the use of novel simian viral vectors to induce T-cell immunity against the more conserved viral antigens. The use of simian vector technology may reflect a major advance as this circumvents the problem of host antivector immunity that may impede vaccine efficacy.

Finally, there are manuscripts that address clinical trials that attempt to improve on existing successes. Rowland and McShane [9] describe clinical studies using a MVA-vectored approach that builds upon the immunity induced by BCG. The article by Kitchin [10] discusses clinical development that aims to maximize the number of vaccines that can be combined in single formulations and strategies to optimize the timing of vaccinations to better fit with the age of cohorts suffering the greatest disease burden.

Therefore, in summary, we think that this issue provides fascinating reading. A broad range of bacterial and viral infectious diseases are covered that are unified by the fact that each represents a major disease burden with enormous clinical need. In each, vaccine development has proceeded successfully to the point of clinical study in man, but efficacy is not yet fully established. We are struck by the innovative approaches that each story represents. As such, these are the diseases and this is work that will continue to dominate the scientific literature in the coming years.

Financial & competing interests disclosure

Eleanor Barnes does not receive any financial support from industry in the form of salary, honoraria or travel assistance. She is funded by the MRC UK. Andrew J Pollard does not currently receive any financial support from industry in the form of honoraria or travel assistance. He acts as chief investigator for clinical trials on behalf of Oxford University funded/sponsored by vaccine manufacturers and his department has received unrestricted educational grants to fund conferences/courses which Andrew J Pollard has organized. Eleanor Barnes and Andrew J Pollard receive funding from the NIHR Oxford Biomedical Research Centre and the NIHR Thames Valley Comprehensive Local Research Network. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.