Elsevier

Current Opinion in Immunology

Volume 41, August 2016, Pages 47-54
Current Opinion in Immunology

Viral vectors as vaccine platforms: from immunogenicity to impact

https://doi.org/10.1016/j.coi.2016.05.014Get rights and content

Highlights

  • Safety and potency of simian adenovirus vectors is now well established, most recently in infants.

  • Viral vectored vaccines are effective against malaria and Ebola in field trials.

  • Protective mechanisms involve both CD8+ T cells and neutralising antibodies.

  • Vaccine manufacture is sufficiently scalable to enable a rapid response to outbreaks.

Viral vectors are the vaccine platform of choice for many pathogens that have thwarted efforts towards control using conventional vaccine approaches. Although the STEP trial encumbered development of recombinant human adenovirus vectors only a few years ago, replication-deficient simian adenoviruses have since emerged as a crucial component of clinically effective prime–boost regimens. The vectors discussed here elicit functionally relevant cellular and humoral immune responses, at extremes of age and in diverse populations. The recent Ebola virus outbreak highlighted the utility of viral vectored vaccines in facilitating a rapid response to public health emergencies. Meanwhile, technological advances in manufacturing to support scale-up of viral vectored vaccines have helped to consolidate their position as a leading approach to tackling ‘old’ and emerging infections.

Introduction

Recombinant viral vectors are a powerful technology for delivering heterologous antigens that combine the best features of other vaccine modalities, with minimal disadvantages. Their capacity to infect cells and express encoded antigens that may be shed into the extracellular milieu or directed to host intracellular processing pathways ensures highly efficient induction of both humoral and cytotoxic (CD8+) T cell responses (Figure 1). This provides a key advantage over subunit vaccines, since CD8+ T cells are critical for the elimination of intracellular pathogens. Viral vectors have intrinsic adjuvant properties, as they express diverse pathogen-associated molecular patterns which activate innate immunity. Targeted gene deletion is a widely used strategy to reduce or eliminate the replicative capacity of viral vectors, which ensures safety for human use without loss of potency. However, some replication-competent viral vectors can also be given safely and may provide equivalent potency at lower doses. The main drawback of viral vector vaccines is that the transgene-specific response may be dampened by pre-existing or de novo adaptive immune responses to antigenic targets within the vector itself. Strategies to overcome this include the use of higher doses, tolerability permitting, and heterologous prime–boost vaccine regimens.

The development of viral vectors as vaccine platforms has continued unabated, in response to the need for new or improved vaccines against known and emerging pathogens. Two viral vectored vaccines are now licensed for human use and others are likely to follow, as the utility of this technology for a rapid response to global health threats is now clearly recognised. We highlight here the most significant progress in the development of viral vectored vaccines in the past five years and the steps taken to address obstacles to their deployment, together with important insights into mechanisms of protective immunity gained from clinical trials.

Section snippets

Pushing the boundaries: immunogenicity across diverse infectious diseases, populations and age groups

Proof of concept for heterologous prime–boost vaccinations was first demonstrated over a decade ago, with experimental vaccines for malaria using DNA and Modified Vaccinia Virus Ankara (MVA) vectors [1, 2]. These early promising results have since been eclipsed by the success of regimens incorporating recombinant adenoviruses as the priming vaccine, thanks to their vastly superior capacity to induce potent cellular and humoral responses. Pre-existing vector-specific immunity, the main drawback

Viral vectored vaccines move into the fast lane

The 2014 West African Ebola virus outbreak accelerated viral vectored vaccines through safety and efficacy testing in transcontinental consortia to identify best-in-class vaccines with unprecedented speed (Figure 2). Replication-competent vesicular stomatitis virus has taken centre stage as a recombinant Zaire Ebola glycoprotein vaccine (VSV-ZEBOV) following phase III clinical trial results from endemic areas that demonstrated remarkable efficacy and impressive antibody titres [19••]. However,

Towards identification of functionally relevant immune responses

The systemic T cell responses elicited by viral vectored vaccines are of sufficiently high magnitude to enable a dissection of the qualitative aspects that may be important for protective immunity. A dominant effector memory phenotype is evident in antigen-specific T cell populations induced by recombinant adenoviruses and poxviruses across vector serotypes, vaccine antigens and animal species [26, 7, 3]. Phenotypic analyses are now routinely complemented with unbiased systems biology

Fulfilling potential: technical advances supporting commercially viable manufacturing and deployment

Limited capacity to deliver vaccines at scale and in resource-limited settings is a perceived disadvantage of viral vectored vaccines; technologies to address this are already in place for replication-deficient adenoviruses [41]. Viral vector production for pre-clinical studies is increased by repression of the transgene during production, typically by use of a cell line that constitutively expresses a tetracyline repressor. However such cell lines were previously not GMP compliant. Procell92®

Conclusions and future directions

Given the overlapping epidemiology of many human pathogens, anti-vector immunity remains a potential challenge if the same vectors are to be used for different targets in a given population. However, it is not insurmountable. Typical doses of most adenoviral vectors are capable of readily overcoming naturally acquired anti-vector immunity to the majority of vaccines, with the exception of now little-used common human adenovirus serotypes. Most of the widely used vectors are designed to be

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors acknowledge the following funding sources for their work: Wellcome Trust, Medical Research Council, Department for International Development, European Union Seventh Framework Programme, Oxford NIHR Biomedical Research Centre. Adrian VS Hill and Lucy Dorrell are Jenner Investigators. The funding sources had no involvement in the design, collection, analysis or interpretation of data, writing or decision to submit this manuscript for publication.

We apologise to those whose important

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