Emerging viruses and current strategies for vaccine intervention.

During the past decade several notable viruses have suddenly emerged from obscurity or anonymity to become serious global health threats, provoking concern regarding their sustained epidemic transmission in immunologically naive human populations. With each new threat comes the call for rapid vaccine development. Indeed, vaccines are considered a critical component of disease prevention for emerging viral infections because, in many cases, other medical options are limited or non-existent, or that infections result in such a rapid clinical deterioration that the effectiveness of therapeutics is limited. While classic approaches to vaccine development are still amenable to emerging viruses, the application of molecular techniques in virology has profoundly influenced our understanding of virus biology, and vaccination methods based on replicating, attenuated and non-replicating virus vector approaches have become useful vaccine platforms. Together with a growing understanding of viral disease emergence, a range of vaccine strategies and international commitment to underpin development, vaccine intervention for new and emerging viruses may become a possibility.

Introduction

Immunization is arguably the most appropriate way of preventing infectious disease. The control of many important viral pathogens by vaccination is perhaps one of the outstanding achievements of medical intervention.

Vaccine‐induced immunity that is established in advance of virus infection relies primarily on adaptive immune responses for protective efficacy. Critically, vaccination depends on the properties of antigen recognition, activation, expansion, memory, trafficking and the multitude of specialist functions of lymphocytes. The extent to which vaccine‐induced immunity is successful also determines the spread and maintenance of a viral pathogen within a population. Viral vaccines have had profound and enduring consequences for human and animal health; the worldwide eradication of smallpox and rinderpest are testament to their outstanding contribution to modern society.

Nevertheless, infectious diseases still pose one of the greatest threats to public health, and the past three decades have brought a constant barrage of new human pathogens. More than 70% of these infections are zoonotic 1, 2, entering either directly from wildlife reservoirs or indirectly via an intermediate domestic animal host 1, 3. HIV, avian influenza, Hendra (HeV) and Nipah (NiV) viruses, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS‐CoV), Ebola and Marburg filoviruses, Lassa virus (LASV), Rift Valley fever virus (RVFV) and Crimean–Congo haemorrhagic fever (CCHF) viruses are all examples of zoonoses currently emerging from wildlife. All these emerging zoonoses present a serious and increasing threat to health, biosecurity and economies worldwide. The mechanisms underlying disease transmission from animals to humans are becoming better understood 4 with the emergence of pathogens from wildlife (which represents the greatest threat to global health) occurring in a non‐uniform pattern, being localized to distinct geographic ‘hotspots’ in Africa, Asia and South America, and with each high‐threat pathogen being weighted towards a key wildlife species (e.g. bats, rodents or non‐human primates (NHPs). It is clear that such diseases will continue to place a substantial burden on global health, especially in dense human populations where the pressures on environmental and economic resources are greatest. More than one billion cases of human zoonotic disease are estimated to occur annually, and emerging zoonoses result in enormous economic losses 5. Increased urbanization, international travel, commerce and climate change increase the likelihood that emerging zoonosis will continue, if not worsen, in the future.

When a zoonotic virus spills over into a susceptible new species, it often has the advantage that the new host has little or no pre‐existing immunity, enabling attachment, entry and replication of the virus in receptive cells. The amplified virus may then evade clearance by host defences for long enough to be transmitted to another susceptible host, and the lack of herd immunity will result in a rapid dissemination of the virus, leading to disease in more virulent cases of infection. Each step in the process represents an opportunity for vaccine‐induced immunity and, through such intervention, transmitters and susceptible hosts are removed from a population by the pre‐emptive development of protective immunity, so that the spread of infection becomes less likely. Vaccination is therefore a powerful strategy for preventing and controlling emerging zoonotic infectious disease. The development of vaccines for such emerging infections, however, needs to contend with several key challenges associated with such viruses. An emerging infection may be a recently discovered virus and the result of a rare outbreak for which basic biological information such as correlates of protection, antigenic variability or immunodominance are unknown. There may be a lack of time to develop an appropriate animal model of disease in which to study viral immunology and evaluate vaccine candidates for preclinical assessment of protective efficacy and safety. Additionally, many emerging viruses have high case fatality rates, spread easily and cannot be treated. These characteristics mandate that all experimental investigations with such infectious material be carried out at high levels of bio‐safety, such as BioSafety levels 3 or 4. For such pathogens the availability of resource‐heavy laboratory infrastructure is a bottleneck to basic research. Moreover, the often standard vaccine approach of using attenuated strains or inactivated viral vaccines is not always a feasible option, because of the possibility of reversion to virulence or the requirement for large‐scale culture and production in high containment facilities. In addition to these significant hurdles, the economic cost of novel human vaccine development for rare pathogens, which are unlikely to provide an effective payback on investment, has been a major impediment to progress. Thus, basic research into many emerging pathogens has been neglected for years.

In 2014 the unpredicted size, speed and reach of the Ebola virus outbreak in West Africa 6 acted as a wake‐up call for researchers, pharmaceutical communities and governments, emphasizing the importance of investment into the study of emerging pathogens. Spurred on by this development and at the request of its 194 Member States in May 2015, the World Health Organization (WHO) convened a broad coalition of experts to develop a research and development (R&D) Blueprint for Action to Prevent Epidemics. Focusing on severe emerging diseases with the potential to generate public health emergencies, and for which no, or insufficient, preventive and curative solutions exist, the R&D Blueprint specifies R&D needs, including vaccine research. Through international governance, the programme aims to define R&D roadmaps for prioritized pathogens and to catalyse funding strategies 7.

Current vaccine platform strategies

Key to the development of successful and effective vaccines is the design of an antigen delivery system that optimizes antigen presentation and induces broad protective immune responses. Recent advances in vector delivery technologies, immunology and basic virology have led to a deeper understanding of the molecular and cellular mechanisms by which vaccines should stimulate both arms of the adaptive immune response, thereby offering novel strategies of vaccination. Here we discuss some current vaccine approaches for safe and effective vaccines encompassing recombinant virus technology, nucleic acid vaccines and self‐disseminating vaccine approaches.

Viral vector technology

Advances in recombinant virology and virus reverse genetics have provided key insights into the replication and pathogenesis of a wide range of viruses. Notably, these have facilitated the development of vectors for protein expression and vaccination. To date, several virus families have been exploited as vectors 8, 9, 10, 11 including many for vaccination 12, 13, 14, 15 Fig 1. A basic advantage of viral vectored vaccines is that the choice antigen is expressed in the context of an active heterologous viral infection, which stimulates the full gamut of innate immune responses required for the development of adaptive humoral and T cell‐mediated immunity 9.

Figure 1

Virus vector platform technologies. Replication competent but attenuated virus vectors (RHS) deliver heterologous antigen targets resulting in the induction of cellular and humoral responses. Their complement of genes enables a full round of replication and assembly of progeny virus which can amplify and spread the vaccine effect to susceptible cells. While these platforms are based on highly attenuated viral backgrounds, replication competence may lead to the development of mutations and reversion to virulence. Replication defective vectors (LHS) support effective cellular entry and a single round of expression of the target gene / antigen; they result in effective induction of cellular and humoral responses. They are unable to generate new infectious progeny and are considered safer than replication competent vectors.

An important aspect of a virus‐vectored vaccine for emerging viruses is that the characteristics, type and intensity of the immune response, as well as safety considerations and manufacturing techniques are determined predominantly by the vector and not the pathogen. Therefore, developing and testing a vaccine against a newly discovered virus can be significantly shortened by the use of a viral vector platform with an extensive record of safety and efficacy.

Replication‐competent (attenuated) viral vectors

Vesicular stomatitis virus (VSV), a negative sense RNA virus of the Rhabdoviridae family, has become a prominent replication‐competent vaccine vector platform 16. VSV is non‐pathogenic in humans and has an inherent ability to elicit strong cellular and humoral immune responses. One of the most useful aspects of this virus vector platform is its almost promiscuous ability to assemble recombinant VSV (rVSV), with many different types of heterologous viral glycoproteins. The platform is designed such that the VSV G protein is replaced with a heterologous envelope glycoprotein from, for example, an emerging virus; while this arrangement renders the rVSV replication competent, the recombinant viruses are generally highly attenuated 17.

In 1937, the attenuation of a yellow fever (YF) virus via successive rounds of serial passage led to the development of the YF vaccine termed 17D. The impact of this successful vaccine was recognized by the award of a Nobel Prize in 1956 18 and it has been widely adopted for human immunization for more than 70 years 19. Based on the utility of the vaccine, an infectious cDNA clone of the YF17D virus 20 has enabled the development of a 17D platform that can be used to drive antigen delivery of pathogens of interest 21. The technology (licenced as ChimeriVax™) is well suited to similarly related flaviviruses and successful recombinants have been constructed, involving a simple swap of the PrM/M‐E genes of YF17D for the same membrane envelope antigens of other emerging flaviviruses, such as Japanese encephalitis, Dengue and West Nile. The resulting recombinant vaccines are efficiently delivered in a live‐attenuated virus context with the safety profile afforded by the 17D non‐structural genes 22. A licenced vaccine for Japanese encephalitis (ChimeriVax™‐JE) using this technology has been developed by Sanofi Pasteur (Lyon, France).

Other replication‐competent platforms

The ease of direct manipulation of viral genomes together with a growing understanding of their biology has led to the development of attenuated virus vaccines with increased safety and immunogenicity. For example, a new vaccine candidate for RVFV has been developed in which a viral virulence factor has been deleted, resulting in a highly attenuated but immunogenic replicating virus 23. A similar recombinant approach has been used to attenuate the emerging and neglected pathogen Mayaro virus (MAYV) by swapping the subgenomic promoter of this alphavirus for an internal ribosome entry site 24, 25, which reduces the expression of MAYV structural proteins. While this arrangement makes the virus unable to infect mosquito cells, replication in mammalian cells is still possible, resulting in a highly immunogenic profile. Similar studies on infectious clones of other viruses 26 have demonstrated that the genomewide de‐optimization of codon usage dramatically reduces gene expression and can be used to attenuate otherwise pathogenic viruses. This strategy has been used for the prototype arenavirus lymphocytic choriomeningitis virus (LCMV) 27; the study showed attenuation in an otherwise fatal mouse model of LCM disease and the ability to induce protective immunity. Together with a maintained and robust ability to multiply in cell culture, this live attenuated approach may be suitable for similar viruses. However, work to underpin confidence in the genetic stability of such attenuated viruses is critical before further consideration can be given to using this approach for clinical intervention, especially considering the inherent high error rates of the arenavirus polymerase.

Replication‐defective approaches

For several years, recombinant adenoviruses have been adopted as promising tools for antigen delivery and vaccine efficacy 28. Deleting the E1 gene from the adenoviral genome and supplying it in trans from a packaging cell line allows replication‐deficient recombinant adenovirus to be produced, with the novel heterologous antigen gene of interest inserted at the E1 locus. Early setbacks in this platform technology relating to pre‐existing anti‐adenovirus vector antibodies in humans 29 have been resolved by adopting simian adenoviruses as vaccine vectors. A number of different replication‐deficient vaccine vectors 30 have recently been developed from simian adenoviruses and the platform has progressed work on emerging pathogens such as Ebola virus, RVFV MERS‐CoV and Zika virus.

Modified vaccinia virus Ankara (MVA) is licensed as a third‐generation vaccinia type vaccine against smallpox and serves as a potent vector system for the development of new candidate vaccines against a range of infectious diseases, including those caused by emerging pathogens. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional vaccinia vaccines 31, 32. Adapted to growth in avian cells, MVA does not replicate in mammalian hosts and lacks many of the viral immune evasion genes 33. The features of MVA, such as its capacity to accommodate large gene inserts 34, thermostability for application in remote regions without an established cold chain 35, ease of inexpensive manufacture to GMP standards and established regulatory package for development as an Investigational New Drug, make the recombinant MVA platform 36 highly versatile as a heterologous viral vector. In the context of emerging infections, the recombinant MVA platform has shown encouraging preclinical efficacy against Ebola, Zika, Chikungunya 37 and CCHF 38 viruses. Additionally, MVA elicits a strong immunological response against a range of other orthopoxviruses (OPXVs) (including Variola), and vaccines based on this platform can be considered as providing added value, as human immunity to OPXVs is low (after the cessation of the smallpox vaccination campaign) opening a gap for OPXV emergence, as evidenced by the recent occurrence of monkeypox virus in West Africa and onward cross boarder transmissions 39, 40.

RNA replicon systems are derived from either positive‐ or negative‐strand RNA virus genomes and embody disabled virus vectors that are non‐pathogenic and unable to revert to virulence. Driven by autonomous RNA replication, RNA replicons result in high‐level, cytosolic expression of recombinant heterologous antigens stimulating both the humoral and cellular arms of the immune system. Replicon vaccine approaches have closely followed technical developments to genetically manipulate viral genomes. For RNA viruses, replicons based on positive‐stranded picornaviruses were some of the first 41, and these were followed by those based on alphaviruses 42 and negative‐strand RNA viruses 43. While a series of different vaccine replicon systems are available, new capabilities with negative‐strand viruses have opened up opportunities against a wider range of emerging viruses. Recent developments 44 include the construction of LASV replicons packaged into LASV‐like particles which allow a single round of replication and are able to confer protection against an otherwise lethal challenge of LASV in a guinea pig model of disease 44. While recombinant replicons are devoid of the viral glycoprotein gene, its incorporation into VLPs is achieved by the use of a cell line that expresses the glycoprotein separately (in trans). This enables the scalable propagation of replicon particles in a way that aims to combine the safety of replicon‐delivered LASV antigens with the convenience of simply and rapidly producing an attenuated virus. Similar replicon approaches have been used to develop promising replicon‐based vaccine candidates for Ebola virus 45 and RVFV 46.

Replicon approaches have the potency of live attenuated vaccines but are inherently safer, as their design ensures a single cycle of replication in contrast to a fully replicating, live attenuated vaccine virus. For live attenuated RNA virus vaccines which incorporate error‐prone polymerases, reversion to virulence is a distinct possibility after multiple rounds of replication.

Virus‐like particles

Interest in the use of virus‐like particles (VLPs) as vaccines candidates stems from their ability to present ordered and highly antigenic structures to the immune system. At the same time, they lack a viral genome, potentially yielding safer vaccines, as there is no viral sequence that can revert to virulence. They induce strong B cell responses in the absence of adjuvants by efficiently cross‐linking specific receptors on B cells 47, and they can also trigger T cell‐mediated responses 48. The basis of ordered viral self‐assembly from protein subunits that is noted in many different virus families provides the foundation for work with VLPs, with more than 30 different viruses that infect humans or other animals being identified as able to produce VLPs. They are structurally diverse, having single or multiple capsid proteins, or a lipid envelope, although not all viruses are suitable VLP candidates. Those which are can elicit a protective response without requiring multiple booster shoots, thus significantly reducing the vaccine costs. To date, VLP‐based vaccines for human papilloma virus (HPV), hepatitis B virus (HBV) and hepatitis E virus (HEV) have been licensed and are commercially available worldwide 49. Several VLP‐based vaccine candidates for human diseases are under clinical development, including those directed against Norwalk virus, Ebola and Marburg viruses and hepatitis C virus. VLP vaccines combine many of the immunogenic advantages of whole‐virus vaccines with the safety advantages of recombinant subunit vaccines.

Nucleic acid vaccines

DNA vaccines have emerged as a safer alternative to standard live and inactivated vaccines for treating human and animal infections 50. They exhibit several advantages over traditional strategies in terms of safety, stability, ease of manufacturing and immunogenicity 51. They offer potential advantages for vaccination against emerging viruses, in that plasmids expressing a viral antigen can be produced rapidly. Furthermore, antigen is expressed in vivo and induces both humoral and cell‐mediated immune responses. Additionally, large quantities of DNA can be produced in a short time at reduced cost, and DNA preparations are more stable than other types of vaccines, which are desirable properties for a vaccine that may be used in remote areas. Furthermore, DNA vaccines are considered safe. However, the main limitation in the development of DNA vaccines is their intrinsic low immunogenicity. Work to improve this has focused on optimizing delivery approaches with the use of gene guns, or electroporation; targeting immune effector cells; and the use of potent adjuvants. DNA vaccines are also frequently used in combination with other vaccine platforms in heterologous prime‐boost strategies.

A DNA vaccine is currently licensed to immunize horses against West Nile virus 52 and has undergone Phase I clinical trials in humans 53. DNA vaccines have also been evaluated as candidates against many emerging viruses, including EBOV 54, RVFV 55, Dengue virus 56 and CHIKV 57.

Synthetic peptides

Synthetic peptide‐based epitope‐vaccines (EVs) make use of short antigen‐derived peptide fragments that can be presented either to T cells or B cells 58. EVs offer several advantages over other forms of vaccines, particularly with regard to safety, ease of production, storage and distribution, without cold chain issues. They also offer the opportunity to vaccinate against several pathogens or multiple epitopes from the same pathogen. However, drawbacks include poor immunogenicity and the restriction of the approach to patients of a given tissue type [human leucocyte antigen (HLA) haplotype] 59 and, as such, they need to be tailored to accommodate the natural variation in HLA genes. Although initially this was thought to be a major impediment, new technologies have made this personalized‐medicine approach feasible 60, 61. Recently, bioinformatics tools have been developed to identify putative CD4+ T cell epitopes, mapped to the surface glycoproteins of the emerging viruses LASV, NipV and Hendra 62. While these vaccine candidates still need to be experimentally tested, the approach represents an interesting and novel strategy that shows promise for vaccination and which could also address immunity in particular target populations.

Inactivated viruses

The induction of immune responses by the delivery of inactivated pathogens has been a standard and successful vaccination approach for many years, and licenced, inactivated vaccines for diseases such as poliomyelitis 63 and rabies 64 are commercially available. The long history of this approach is underpinned by a well‐defined regulatory framework that can be readily applied to new disease targets 65. The major challenge for the inactivated virus approach is that infection is not established, and therefore a full adaptive immune response is generally not achieved. However, because of the absence of living pathogens, these types of vaccines are safe and a basic capability to prepare such vaccines, especially for emergency use, might be worthwhile as a stop‐gap while alternative longer‐term approaches are developed. In this regard, studies of virus inactivation with X‐ray radiation (as a simple and cheap alternative to gamma irradiation by the use of radioactive isotopes), which maintain the tertiary antigenic structures of virus particles while destroying infectivity, have shown useful promise for a range of applications including vaccination (B. Afrough, unpublished).

Future perspectives

Vaccines play a pivotal role in host protection against infectious diseases and have significantly reduced mortality worldwide. However, many vaccine candidates for emerging diseases have failed to make it into clinical development. This is perhaps surprising, given the breadth of vaccine technology available and the nature of many of the diseases in question. A case in point is Lassa fever, a viral haemorrhagic illness endemic to many parts of West Africa responsible for more than 300 000 cases of serious disease and approximately 3000 deaths each year since its discovery more than 50 years ago. It is often in the headlines, being the most commonly exported VHF to other territories, including the United Kingdom, which has received a disproportionate share of traveller‐related cases (each incident placing substantial burden on public health resources). During 2018, LASV caused an unusually large increase in cases in Nigeria, which led the WHO to classify it as a grade 2 public health emergency. However, despite the high burden of Lassa fever and public attention, no vaccines have so far been approved. Multiple approaches to develop a range of effective preclinical candidates have been made during the last three decades, including attenuated vaccines 66, replication competent vaccines, 67, 68, 69, non‐replicating LASV vaccines 47, a rationally designed live attenuated vaccine 70 and DNA vaccines 71. Additionally, many of these platforms have shown efficacy in animal models including NHPs 67, 72, 73.

These preclinical data illustrate that multiple vaccine technologies have the potential to yield protective Lassa fever vaccines. Therefore, the lack of a clinical vaccine after 50 years since the disease was first described must be due to other factors, such as economic considerations or safety issues, perhaps connected with the growing burden of regulatory thresholds for human medical interventions. Thus, bringing a LASV vaccine and, by analogy, other potential vaccines for emerging diseases to the clinic, may be very difficult – for non‐technical reasons. Although there is renewed interest from multiple international agencies to develop human vaccines for certain emerging pathogens 74, 75, it is prudent to consider other approaches to the control of emerging disease, including the feasibility of controlling infections at source.

The pattern of disease emergence from viral pathogens into humans from wildlife reservoirs is a clear and present threat 1, 2, 3, 4, 5 which will continue. This makes the task of identifying, controlling and preventing zoonoses a difficult and daunting goal, particularly when a new emerging pathogen may be completely unknown. While surveillance is an essential component of a successful control programme, effective containment of an emerging pathogen, before epizootics have the opportunity to spill over into human populations, has been achieved most effectively by large‐scale culling or mass vaccination 76, 77 of animals. Nevertheless, the ability to contain even known emerging viruses such as Ebola virus in wildlife is currently not possible. Furthermore, the management of diseases that involve livestock, such as RVF and CCHF, pose problems 78, 79 in that conventional vaccines are not suited for use in these environments. A major limitation of conventional vaccination is the requirement for individual inoculation of each animal – a costly and impractical strategy for the target/reservoir species of those animals frequently involved in the emergence of high‐risk pathogens 1.

Surveillance work focusing on epizootics that are, or may become, human pathogens is a useful goal. Currently however, predicting which animal pathogens will become established as globally significant emerging human diseases is guesswork. Nevertheless, in the early stages of a new zoonosis, pathogenic viruses are often poorly adapted to their new human host in terms of sustained human‐to‐human transmission 80. This lag‐phase in early zoonosis may, therefore, provide a window of opportunity to control the unrelenting zoonotic pressure of an emerging pathogen before it adapts further to humans. Vaccine targeting of the pathogen within the animal transmission species could therefore bring useful advantages.

Self‐disseminating wild‐life reservoir vaccines

Self‐disseminating vaccines, which aim to immunologically contain emerging viruses within their non‐human reservoir hosts, offer an alternative to the conventional vaccine approach. They are designed to exploit the ability of replicating virus‐based vectors to spread through animal host populations, so avoiding the need for direct inoculation of every animal. In this way, vaccination of a limited number of initiator animals is used for the introduction of the vaccine into a target population. The vaccine is engineered to express target antigens from the emerging pathogen of interest, so its transmission from vaccinated to non‐vaccinated animals will result in the co‐ordinated spread of specific immunity for the emerging pathogen throughout the targeted animal population.

Following early work to underpin a proof of principle for a disseminating vaccine against an animal pathogen 81, 82, a study targeting the human pathogen Sin Nombre orthohantavirus (SNV) in its rodent reservoir – the deer mouse (Peromyscus maniculatus) – proved effective. This approach used an engineered cytomegalovirus (CMV) vector (which causes a benign but transmissible infection in the host), expressing the SNV envelope glycoprotein G1 83. A similar approach is also being developed to interrupt zoonotic transmission of Ebola virus 84, in this case disseminating CMV vaccines specific to great apes and expressing EBOV antigens are being studied in African ape populations in the wild 85. Interestingly, one of the goals of this work is to protect the great apes themselves from Ebola virus disease, a major threat to the survival of these animals in the wild. Also, as approximately 30% of human Ebola virus outbreaks are known to have resulted from the direct handling of infected ape carcasses, the disseminating CMV‐based strategy may be significant in protecting humans 86. Clearly, further work needs to be conducted to assess the risks of live transmissible vaccines evolving into a pathogen with increased virulence. Engineering such wild‐life reservoir vaccines to be weakly transmitting, such that their reproduction number is below 1 (R 0 < 1), making their transmission chains short so that they cannot be maintained, might be a way to address the justifiable safety risks. Indeed, a mathematical model has recently demonstrated the value of such an approach 87.

Conclusions

Emerging pathogens represent one of the greatest risks to global health. There is already good evidence 1, 5 that zoonotic pathogens will most probably be transmitted from a few key animal species in resource‐poor areas of the world. Based on recent history, it is probable that such pathogens have never been seen before. The global impact of the West African outbreak of Ebola virus in 2014 underlines how stark differences in health‐care infrastructure can impact upon human‐to‐human transmission of emerging pathogens. Until basic health‐care infrastructure in all countries can be raised to a level that enables early identification and control of high‐risk pathogens at source, we will continue to respond to outbreaks of emerging disease long after epizootics have spilled over into human populations. Innovative strategies are therefore urgently required to control such pathogens, vaccination is a proven approach.

Many novel vaccination strategies that have been developed during recent years have the potential to specifically address the growing threat of new and emerging disease. The use of well‐defined vaccine vector platforms, with an extensive record of safety and efficacy against similar pathogens, can expedite the process of development, validation and production (Table 1). Accordingly, the design and licensure for particular platform vaccine technologies will help to accelerate the development of new vaccines, as only the simple substitution of a new antigen gene into the vector platform is required. This allows manufacturers to move to a new target disease with minimal changes in chemistry, manufacturing and controls. Thus, new vaccine development can focus on the safety and efficacy of the inserted gene. In addition, the ability of platforms to target multiple pathogens helps to justify the investment required to build and maintain manufacturing infrastructure that specializes in one platform, because a single manufacturing facility can be ready to produce multiple vaccines at any time.

Table 1

Relative advantages/disadvantages of listed vaccine platform technologies

Platform	Benefits	Disadvantages
Viral vector	Development of good humoral and T cell responses	Selective pressures may result in reduced expression or loss of heterologous antigens or in some case reversion to virulence
Replication‐competent	Several platforms available. Simple production via virus culture
Viral vector	Safe. Development of good humoral and T cell responses	Production may require additional steps and cell lines
Replication‐defective
Virus‐like particles	Good induction of humoral and T cell responses. Safe	Production costs may be high and require multiple steps
Naked nucleic acid	Safe. Rapid construction/production	Lower levels of inducted immune responses
Synthetic peptides	Safe. Ease of production and storage	Uncertain immunogenicity linked to target populations
Inactivated viruses	Safe. Well‐defined regulatory framework	Questionable (but sometimes effective) immunogenicity
Self‐disseminating wild‐life vaccines	Sustained transmission within EID reservoir populations, avoiding individual inoculation	Selective pressures may lead to a possible development of virulence

In addition, further research into, and the development of, self‐disseminating vaccines to control potential pathogens in their wild‐life reservoirs should be encouraged. However, the progress of new vaccines through the necessary regulatory pathways to bring them to the clinic requires long‐term investment by governments and international organizations.

Disclosures

The authors confirm that they have no competing interests in this work.