Current status of virus-vectored vaccines against pathogens that affect poultry

The most effective strategies for the control of disease in poultry are vaccination and biosecurity. Vaccines useful against pathogens affecting poultry must be safe, effective with a single dose, inexpensive, applicable by mass vaccination methods, and able to induce a protective immune response in the presence of maternal antibodies. Viral vector meet some of these characteristics and if the attenuated virus used as vector infects birds, the vaccine will have the advantage of being bivalent. Thus, viral vectors are currently a tool of choice for the development of new poultry vaccines. This review describes the main viruses used as vectors for the delivery and in vivo expression of antigens of poultry pathogens. It also presents the methodologies most frequently used to obtain recombinant viral vectors and summarizes the state-of-the-art related to vectored vaccines in poultry (some of them currently licensed), the pathogens targeted and their antigens, and the ability of these vaccines to induce an effective immune response. Finally, the review discusses the results of a few studies comparing recombinant viral vector vaccines and live-attenuated vaccines in vaccine matching challenges, and mentions strategies and future researches that can help to improve the efficacy of vectored vaccines in poultry birds.     

Third-generation smallpox vaccine strain-based recombinant vaccines for viral hemorrhagic fevers

Vaccinia virus has been used as a smallpox vaccine. Now that smallpox has been eradicated, the vaccinia virus is expected to be used as a bioterrorism countermeasure and a recombinant vaccine vector for other infectious diseases, such as viral hemorrhagic fevers. Many vaccinia virus strains were used as smallpox vaccines in the smallpox eradication campaign coordinated by the World Health Organization. These strains can be classified into generations, according to the history of improving production methods and efforts to reduce the adverse reactions. Significantly, the third-generation of smallpox vaccine strains, which include modified vaccinia Ankara (MVA) and LC16m8, are currently popular as recombinant vaccine vectors due to their well-balanced safety and immunogenicity profiles. The present review firstly focuses on the characteristics of the smallpox vaccine generations. The historical background of the development of the third-generation smallpox vaccine strains is detailed, along with the history of the transition of the vaccinia virus generation used as vectors for hemorrhagic fever vaccines to the third generation. Among the vaccinia viruses, MVA is currently the most commonly used vector for developing hemorrhagic fever vaccines, including dengue fever, yellow fever, Ebola viral disease, Lassa fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever. LC16m8 is a vaccine candidate for severe fever with thrombocytopenia syndrome. The current status and recent advances in the development of these hemorrhagic fever vaccines using third-generation vaccinia strains are discussed.     

Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called “chimeric virus vaccines”). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.     

Live virus vaccines based on a yellow fever vaccine backbone: Standardized template with key considerations for a risk/benefit assessment

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so-called “chimeric virus vaccines”). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.     

Tailoring subunit vaccine immunogenicity: maximizing antibody and T cell responses by using combinations of adenovirus, poxvirus and protein-adjuvant vaccines against Plasmodium falciparum MSP1

Subunit vaccination modalities tend to induce particular immune effector responses. Viral vectors are well known for their ability to induce strong T cell responses, while protein-adjuvant vaccines have been used primarily for induction of antibody responses. Here, we demonstrate in mice using a Plasmodium falciparum merozoite surface protein 1 (PfMSP1) antigen that novel regimes combining adenovirus and poxvirus vectored vaccines with protein antigen in Montanide ISA720 adjuvant can achieve simultaneous antibody and T cell responses which equal, or in some cases surpass, the best immune responses achieved by either the viral vectors or the protein vaccine alone. Such broad responses can be achieved either using three-stage vaccination protocols, or with an equally effective two-stage protocol in which viral vectors are admixed with protein and adjuvant, and were apparent despite the use of a protein antigen that represented only a portion of the viral vector antigen. We describe further possible advantages of viral vectors in achieving consistent antibody priming, enhanced antibody avidity, and cytophilic isotype skew. These data strengthen the evidence that tailored combinations of vaccine platforms can achieve desired combinations of immune responses, and further encourage the co-administration of antibody-inducing recombinant protein vaccines with T cell- and antibody-inducing recombinant viral vectors as one strategy that may achieve protective blood-stage malaria immunity in humans.     

New vaccines against hepatitis B

The high cost and limited availability of the plasma-derived hepatitis B vaccines have prevented their widespread use, especially in the less developed areas where they are needed most. Hepatitis B vaccines produced by recombinant technology seem to offer a solution to these difficulties. Studies reported up to now confirmed the safety of this vaccine. Immunogenicity studies in various population groups showed that seroconversion rates and antibody titres are comparable to plasma vaccine. In assessing the efficacy of the vaccine, information concerning the quality of the anti-HBs induced should complement these data. Potential live vaccines using recombinant vaccinia viruses have been constructed for hepatitis .B. Preliminary studies in rabbits and chimpanzees indicated the feasibility of future using a recombinant vaccinia virus.Chemically synthesized polypeptides corresponding to relevant epitopes of HBsAg may be useful as synthetic vaccines offering the advantages of a cheap viral immunogen free from irrelevant antigenic determinants.Finally preliminary studies for an idiotypic vaccine have already been reported.     

RNA-based vaccines

Nucleic acid vaccines consisting of plasmid DNA, viral vectors or RNA may change the way the next generation vaccines are produced, as they have the potential to combine the benefits of live-attenuated vaccines, without the complications often associated with live-attenuated vaccine safety and manufacturing. Over the past two decades, numerous clinical trials of plasmid DNA and viral vector-based vaccines have shown them to be safe, well-tolerated and immunogenic. Yet, sufficient potency for general utility in humans has remained elusive for DNA vaccines and the feasibility of repeated use of viral vectors has been compromised by anti-vector immunity. RNA vaccines, including those based on mRNA and self-amplifying RNA replicons, have the potential to overcome the limitations of plasmid DNA and viral vectors. Possible drawbacks related to the cost and feasibility of manufacturing RNA vaccines are being addressed, increasing the likelihood that RNA-based vaccines will be commercially viable. Proof of concept for RNA vaccines has been demonstrated in humans and the prospects for further development into commercial products are very encouraging.     

Recombinant MVA vaccines: dispelling the myths

Diseases such as HIV/AIDS, tuberculosis, malaria and cancer are prime targets for prophylactic or therapeutic vaccination, but have proven partially or wholly resistant to traditional approaches to vaccine design. New vaccines based on recombinant viral vectors expressing a foreign antigen are under intense development for these and other indications. One of the most advanced and most promising vectors is the attenuated, non-replicating poxvirus MVA (modified vaccinia virus Ankara), a safer derivative of the uniquely successful smallpox vaccine. Despite the ability of recombinant MVA to induce potent humoral and cellular immune responses against transgenic antigen in humans, especially when used as the latter element of a heterologous prime-boost regimen, doubts are occasionally expressed about the ultimate feasibility of this approach. In this review, five common misconceptions over recombinant MVA are discussed, and evidence is cited to show that recombinant MVA is at least sufficiently genetically stable, manufacturable, safe, and immunogenic (even in the face of prior anti-vector immunity) to warrant reasonable hope over the feasibility of large-scale deployment, should useful levels of protection against target pathogens, or therapeutic benefit for cancer, be demonstrated in efficacy trials.     

Evaluating the promise of recombinant transmissible vaccines

Transmissible vaccines have the potential to revolutionize infectious disease control by reducing the vaccination effort required to protect a population against a disease. Recent efforts to develop transmissible vaccines focus on recombinant transmissible vaccine designs (RTVs) because they pose reduced risk if intra-host evolution causes the vaccine to revert to its vector form. However, the shared antigenicity of the vaccine and vector may confer vaccine-immunity to hosts infected with the vector, thwarting the ability of the vaccine to spread through the population. We build a mathematical model to test whether a RTV can facilitate disease management in instances where reversion is likely to introduce the vector into the population or when the vector organism is already established in the host population, and the vector and vaccine share perfect cross-immunity. Our results show that a RTV can autonomously eradicate a pathogen, or protect a population from pathogen invasion, when cross-immunity between vaccine and vector is absent. If cross-immunity between vaccine and vector exists, however, our results show that a RTV can substantially reduce the vaccination effort necessary to control or eradicate a pathogen only when continuously augmented with direct manual vaccination. These results demonstrate that estimating the extent of cross-immunity between vector and vaccine is a critical step in RTV design, and that herpesvirus vectors showing facile reinfection and weak cross-immunity are promising.     

Biosecurity risks associated with vaccine platform technologies

Vaccine platforms have been critical for accelerating the timeline of COVID-19 vaccine development. Faster vaccine timelines demand further development of these technologies. Currently investigated platform approaches include virally vectored and RNA-based vaccines, as well as DNA vaccines and recombinant protein expression system platforms, each featuring different advantages and challenges. Viral vector-based and DNA vaccines in particular have received a large share of research funding to date. Platform vaccine technologies may feature dual-use potential through informing or enabling pathogen engineering, which may raise the risk for the occurrence of deliberate, anthropogenic biological events. Research on virally vectored vaccines exhibits relatively high dual-use potential for two reasons. First, development of virally vectored vaccines may generate insights of particular dual-use concern such as techniques for circumventing pre-existing anti-vector immunity. Second, while the amount of work on viral vectors for gene therapy exceeds that for vaccine research, work on virally vectored vaccines may increase the number of individuals capable of engineering viruses of particular concern, such as ones closely related to smallpox. Other platform vaccine approaches, such as RNA vaccines, feature relatively little dual-use potential. The biosecurity risk associated with platform advancement may be minimised by focusing preferentially on circumventing anti-vector immunity with non-genetic rather than genetic modifications, using vectors that are not based on viruses pathogenic to humans, or preferential investment into promising RNA-based vaccine approaches. To reduce the risk of anthropogenic pandemics, structures for the governance of biotechnology and life science research with dual-use potential need to be reworked. Scientists outside of the pathogen research community, for instance those who work on viral vectors or oncolytic viruses, need to become more aware of the dual-use risks associated with their research. Both public and private research-funding bodies need to prioritise the evaluation and reduction of biosecurity risks.     

Immunogenicity and protective efficacy of recombinant Modified Vaccinia virus Ankara candidate vaccines delivering West Nile virus envelope antigens

West Nile virus (WNV) cycles between insects and wild birds, and is transmitted via mosquito vectors to horses and humans, potentially causing severe neuroinvasive disease. Modified Vaccinia virus Ankara (MVA) is an advanced viral vector for developing new recombinant vaccines against infectious diseases and cancer. Here, we generated and evaluated recombinant MVA candidate vaccines that deliver WNV envelope (E) antigens and fulfil all the requirements to proceed to clinical testing in humans. Infections of human and equine cell cultures with recombinant MVA demonstrated efficient synthesis and secretion of WNV envelope proteins in mammalian cells non-permissive for MVA replication. Prime-boost immunizations in BALB/c mice readily induced circulating serum antibodies binding to recombinant WNV E protein and neutralizing WNV in tissue culture infections. Vaccinations in HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice elicited WNV E-specific CD8+ T cell responses. Moreover, the MVA–WNV candidate vaccines protected C57BL/6 mice against lineage 1 and lineage 2 WNV infection and induced heterologous neutralizing antibodies. Thus, further studies are warranted to evaluate these recombinant MVA–WNV vaccines in other preclinical models and use them as candidate vaccine in humans.     

Vaccines based on replication incompetent Ad26 viral vectors: Standardized template with key considerations for a risk/benefit assessment

Replication-incompetent adenoviral vectors have been under investigation as a platform to carry a variety of transgenes, and express them as a basis for vaccine development. A replication-incompetent adenoviral vector based on human adenovirus type 26 (Ad26) has been evaluated in several clinical trials.The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and features of recombinant viral vector vaccines. This paper reviews features of the Ad26 vectors, including tabulation of safety and risk assessment characteristics of Ad26-based vaccines.In the Ad26 vector, deletion of E1 gene rendering the vector replication incompetent is combined with additional genetic engineering for vaccine manufacturability and transgene expression optimization. These vaccines can be manufactured in mammalian cell lines at scale providing an effective, flexible system for high-yield manufacturing. Ad26 vector vaccines have favorable thermostability profiles, compatible with vaccine supply chains.Safety data are compiled in the Ad26 vaccine safety database version 4.0, with unblinded data from 23 ongoing and completed clinical studies for 3912 participants in five different Ad26-based vaccine programs. Overall, Ad26-based vaccines have been well tolerated, with no significant safety issues identified. Evaluation of Ad26-based vaccines is continuing, with >114,000 participants vaccinated as of 4th September 2020.Extensive evaluation of immunogenicity in humans shows strong, durable humoral and cellular immune responses. Clinical trials have not revealed impact of pre-existing immunity to Ad26 on vaccine immunogenicity, even in the presence of Ad26 neutralizing antibody titers or Ad26-targeting T cell responses at baseline.The first Ad26-based vaccine, against Ebola virus, received marketing authorization from EC on 1st July 2020, as part of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. New developments based on Ad26 vectors are underway, including a COVID-19 vaccine, which is currently in phase 3 of clinical evaluation.     

Utilizing poxviral vectored vaccines for antibody induction—Progress and prospects

Over the last decade, poxviral vectors emerged as a mainstay approach for the induction of T cell-mediated immunity by vaccination, and their suitability for human use has led to widespread clinical testing of candidate vectors against infectious intracellular pathogens and cancer. In contrast, poxviruses have been widely perceived in the vaccine field as a poor choice of vector for the induction of humoral immunity. However, a growing body of data, from both animal models and recent clinical trials, now suggests that these vectors can be successfully utilized to prime and boost B cells and effective antibody responses. Significant progress has been made in the context of heterologous prime–boost immunization regimes, whereby poxviruses are able to boost responses primed by other vectors, leading to the induction of high-titre antigen-specific antibody responses. In other cases, poxviral vectors have been shown to stimulate humoral immunity against both themselves and encoded transgenes, in particular viral surface proteins such as influenza haemagglutinin. In the veterinary field, recombinant poxviral vectors have made a significant impact with numerous vectors licensed for use against a variety of animal viruses. On-going studies continue to explore the potential of poxviral vectors to modulate qualitative aspects of the humoral response, as well as their amenability to adjuvantation seeking to improve quantitative antibody immunogenicity. Nevertheless, the underlying mechanisms of B cell induction by recombinant poxviruses remain poorly defined, and further work is necessary to help guide the rational optimization of future poxviral vaccine candidates aiming to induce antibodies.     

Viral and bacterial vectors of immunogenes

A recent development in the production of experimental vaccines has been the use of the smallpox vaccine virus (vaccinia virus) as a carrier (vector) of the genes (immunogenes) which code for the protection-inducing proteins (immunogens) of unrelated viruses. The potential of these vector vaccines lies in the hope that such a vaccine would be cheaper, safer and/or more effective than existing vaccines to some pathogens. Vaccinia virus as a vector has attracted most attention to date because: several immunogenes can be inserted into its genome without destroying its infectivity; the immunogens appear to be produced normally; vaccinia virus has been used highly successfully to eradicate smallpox; and it has a wide host-range and thus might find veterinary as well as human medical application. Experimental vaccines, successfully tested in animals, have been prepared using immunogenes from influenza virus, hepatitis B virus and herpes simplex virus. Apathogenic enteric bacteria have some potential as vectors, most probably against enteric pathogens, although the potential of viral vectors is likely to be realized first. Parasitic worms and protozoa devastate millions of people. When the immunogens of these organisms have been identified there will be added impetus to investigate the potential of vector vaccines against these pathogens.     

Virus-like particles as a highly efficient vaccine platform: Diversity of targets and production systems and advances in clinical development

Virus-like particles (VLPs) are a class of subunit vaccines that differentiate themselves from soluble recombinant antigens by stronger protective immunogenicity associated with the VLP structure. Like parental viruses, VLPs can be either non-enveloped or enveloped, and they can form following expression of one or several viral structural proteins in a recombinant heterologous system. Depending on the complexity of the VLP, it can be produced in either a prokaryotic or eukaryotic expression system using target-encoding recombinant vectors, or in some cases can be assembled in cell-free conditions. To date, a wide variety of VLP-based candidate vaccines targeting various viral, bacterial, parasitic and fungal pathogens, as well as non-infectious diseases, have been produced in different expression systems. Some VLPs have entered clinical development and a few have been licensed and commercialized. This article reviews VLP-based vaccines produced in different systems, their immunogenicity in animal models and their status in clinical development.     

A simple and rapid approach to develop recombinant avian herpesvirus vectored vaccines using CRISPR/Cas9 system

Herpesvirus of turkeys (HVT) has been successfully used as live vaccine against Marek's disease (MD) worldwide for more than 40 years either alone or in combination with other serotypes. HVT is also widely used as a vector platform for generation of recombinant vaccines against a number of avian diseases such as infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) using conventional recombination methods or recombineering tools on cloned viral genomes. In the present study, we describe the application of CRISPR/Cas9-based genome editing as a rapid and efficient method of generating HVT recombinants expressing VP2 protein of IBDV. This approach offers an efficient method to introduce other viral antigens into the HVT genome for rapid development of recombinant vaccines.     

The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. The Modified Vaccinia Ankara (MVA) vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features specifically of the MVA-BN vector system, followed by a template with details on the safety and characteristics of an MVA-BN based vaccine against Zaire ebolavirus and other filovirus strains. The MVA-BN-Filo vaccine is based on a live, highly attenuated poxviral vector incapable of replicating in human cells and encodes glycoproteins of Ebola virus Zaire, Sudan virus and Marburg virus and the nucleoprotein of the Thai Forest virus. This vaccine has been approved in the European Union in July 2020 as part of a heterologous Ebola vaccination regimen. The MVA-BN vector is attenuated following over 500 serial passages in eggs, showing restricted host tropism and incompetence to replicate in human cells. MVA has six major deletions and other mutations of genes outside these deletions, which all contribute to the replication deficiency in human and other mammalian cells. Attenuation of MVA-BN was demonstrated by safe administration in immunocompromised mice and non-human primates. In multiple clinical trials with the MVA-BN backbone, more than 7800 participants have been vaccinated, demonstrating a safety profile consistent with other licensed, modern vaccines. MVA-BN has been approved as smallpox vaccine in Europe and Canada in 2013, and as smallpox and monkeypox vaccine in the US in 2019. No signal for inflammatory cardiac disorders was identified throughout the MVA-BN development program. This is in sharp contrast to the older, replicating vaccinia smallpox vaccines, which have a known risk for myocarditis and/or pericarditis in up to 1 in 200 vaccinees. MVA-BN-Filo as part of a heterologous Ebola vaccination regimen (Ad26.ZEBOV/MVA-BN-Filo) has undergone clinical testing including Phase III in West Africa and is currently in use in large scale vaccination studies in Central African countries. This paper provides a comprehensive picture of the MVA-BN vector, which has reached regulatory approvals, both as MVA-BN backbone for smallpox/monkeypox, as well as for the MVA-BN-Filo construct as part of an Ebola vaccination regimen, and therefore aims to provide solutions to prevent disease from high-consequence human pathogens.     

Reflections on the early development of poxvirus vectors

Poxvirus expression vectors were described in 1982 and quickly became widely used for vaccine development as well as research in numerous fields. Advantages of the vectors include simple construction, ability to accommodate large amounts of foreign DNA and high expression levels. Numerous poxvirus-based veterinary vaccines are currently in use and many others are in human clinical trials. The early reports of poxvirus vectors paved the way for and stimulated the development of other viral vectors and recombinant DNA vaccines.     

Inclusion of the murine IgGκ signal peptide increases the cellular immunogenicity of a simian adenoviral vectored Plasmodium vivax multistage vaccine

IntroductionCellular and humoral immune responses are both involved in protection against Plasmodium infections. The only malaria vaccine available, RTS,S, primarily induces short-lived antibodies and targets only a pre-erythrocytic stage antigen. Inclusion of erythrocytic stage targets and enhancing cellular immunogenicity are likely necessary for developing an effective second-generation malaria vaccine. Adenovirus vectors have been used to improve the immunogenicity of protein-based vaccines. However, the clinical assessment of adenoviral-vectored malaria vaccines candidates has shown the induction of robust Plasmodium-specific CD8+ but not CD4+ T cells. Signal peptides (SP) have been used to enhance the immunogenicity of DNA vaccines, but have not been tested in viral vector vaccine platforms.ObjectivesThe objective of this study was to determine if the addition of the SP derived from the murine IgGκ light chain within a recombinant adenovirus vector encoding a multistage P. vivax vaccine candidate could improve the CD4+ T cell response.MethodsIn this proof-of-concept study, we immunized CB6F1/J mice with either the recombinant simian adenovirus 36 vector containing the SP (SP-SAd36) upstream from a transgene encoding a chimeric P. vivax multistage protein or the same SAd36 vector without the SP. Mice were subsequently boosted twice with the corresponding recombinant proteins emulsified in Montanide ISA 51 VG. Immunogenicity was assessed by measurement of antibody quantity and quality, and cytokine production by T cells after the final immunization.ResultsThe SP-SAd36 immunization regimen induced significantly higher antibody avidity against the chimeric P. vivax proteins tested and higher frequencies of IFN-γ and IL-2 CD4+ and CD8+ secreting T cells, when compared to the unmodified SAd36 vector.ConclusionsThe addition of the murine IgGκ signal peptide significantly enhances the immunogenicity of a SAd36 vectored P. vivax multi-stage vaccine candidate in mice. The potential of this approach to improve upon existing viral vector vaccine platforms warrants further investigation.     

Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver.The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world.We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV.The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1.