Viral vectors as vaccine platforms: from immunogenicity to impact
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.
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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
References (61)
- et al.
Safety of DNA and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers
Vaccine
(2003) - et al.
A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory
Sci Transl Med
(2014) - et al.
Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults
Sci Transl Med
(2015) - et al.
Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya
PLoS ONE
(2007) - et al.
Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy
Vaccine
(2008) - et al.
The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8 T cell responses
Vaccine
(2014) - et al.
Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial
Lancet
(2015) - et al.
Phase 1 trials of rVSV Ebola vaccine in Africa and Europe — preliminary report
N Engl J Med
(2015) - et al.
Efficacy and long-term safety of a dengue vaccine in regions of endemic disease
N Engl J Med
(2015) - et al.
Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms
Science
(2013)
AAV's Golden Jubilee
Mol Ther
Enhanced vaccine-induced CD8+ T cell responses to malaria antigen ME-TRAP by fusion to MHC class II invariant chain
PLOS ONE
Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice
PLOS ONE
Carbohydrate-based ice recrystallization inhibitors increase infectivity and thermostability of viral vectors
Sci Rep
Immunogenicity and efficacy of a chimpanzee adenovirus-vectored Rift Valley Fever vaccine in mice
Virol J
Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals
J Infect Dis
A recombinant vesicular stomatitis virus Ebola vaccine — preliminary report
N Engl J Med
Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans
Nat Med
Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector
J Infect Dis
Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation
Nat Commun
Prime–boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults
Sci Transl Med
Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1
Mol Ther
Clinical assessment of a novel recombinant simian adenovirus ChAdOx1 as a vectored vaccine expressing conserved influenza A antigens
Mol Ther
A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP + M1 in adults aged over 50 years
PLoS ONE
Efficacy of high-dose versus standard-dose influenza vaccine in older adults
N Engl J Med
Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy
Epidemiol Infect
Coadministration of seasonal influenza vaccine and MVA-NP + M1 simultaneously achieves potent humoral and cell-mediated responses
Mol Ther
Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells
Eur J Immunol
Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial
Lancet
A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA
N Engl J Med
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