Viral vectors as vaccine platforms: from immunogenicity to impact

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

Chimpanzee adenoviral vectors as vaccines for outbreak pathogens

The 2014-15 Ebola outbreak in West Africa highlighted the potential for large disease outbreaks caused by emerging pathogens and has generated considerable focus on preparedness for future epidemics. Here we discuss drivers, strategies and practical considerations for developing vaccines against outbreak pathogens. Chimpanzee adenoviral (ChAd) vectors have been developed as vaccine candidates for multiple infectious diseases and prostate cancer. ChAd vectors are safe and induce antigen-specific cellular and humoral immunity in all age groups, as well as circumventing the problem of pre-existing immunity encountered with human Ad vectors. For these reasons, such viral vectors provide an attractive platform for stockpiling vaccines for emergency deployment in response to a threatened outbreak of an emerging pathogen. Work is already underway to develop vaccines against a number of other outbreak pathogens and we will also review progress on these approaches here, particularly for Lassa fever, Nipah and MERS

Chimpanzee adenoviral vectors as vaccines for outbreak pathogens

The 2014-15 Ebola outbreak in West Africa highlighted the potential for large disease outbreaks caused by emerging pathogens and has generated considerable focus on preparedness for future epidemics. Here we discuss drivers, strategies and practical considerations for developing vaccines against outbreak pathogens. Chimpanzee adenoviral (ChAd) vectors have been developed as vaccine candidates for multiple infectious diseases and prostate cancer. ChAd vectors are safe and induce antigen-specific cellular and humoral immunity in all age groups, as well as circumventing the problem of pre-existing immunity encountered with human Ad vectors. For these reasons, such viral vectors provide an attractive platform for stockpiling vaccines for emergency deployment in response to a threatened outbreak of an emerging pathogen. Work is already underway to develop vaccines against a number of other outbreak pathogens and we will also review progress on these approaches here, particularly for Lassa fever, Nipah and MERS

CXCR3+ T follicular helper cells induced by co-administration of RTS,S/AS01B and viral vectored vaccines are associated with reduced immunogenicity and efficacy against Malaria

Malaria remains a significant cause of morbidity and mortality in sub-Saharan Africa. An efficacious vaccine will be an essential part of attempts to eradicate the disease. A vaccine strategy targeting multiple stages lifecycle stages may be required to achieve a high level of efficacy. In a series of phase IIa clinical trials we tested different regimens of two vaccine platforms: RTS,S/AS01B, which induces antibody responses to target sporozoites and viral-vectored vaccines ChAd63-MVA ME-TRAP, which induce T cells that target infected hepatocytes. Concomitant administration of these vaccines significantly reduced humoral immunogenicity and protective efficacy against controlled human malaria infection. Strong Th1 cytokine responses induced by MVA ME-TRAP were associated with a skew in circulating T follicular helper cells towards a CXCR3+ phenotype and the observed reduction in antibody quantity and quality. This study illustrates that while a multistage-targeting vaccine strategy could provide high-level efficacy, the regimen design will require careful optimisation

CXCR3+ T follicular helper cells induced by co-administration of RTS,S/AS01B and viral vectored vaccines are associated with reduced immunogenicity and efficacy against Malaria

Malaria remains a significant cause of morbidity and mortality in sub-Saharan Africa. An efficacious vaccine will be an essential part of attempts to eradicate the disease. A vaccine strategy targeting multiple stages lifecycle stages may be required to achieve a high level of efficacy. In a series of phase IIa clinical trials we tested different regimens of two vaccine platforms: RTS,S/AS01B, which induces antibody responses to target sporozoites and viral-vectored vaccines ChAd63-MVA ME-TRAP, which induce T cells that target infected hepatocytes. Concomitant administration of these vaccines significantly reduced humoral immunogenicity and protective efficacy against controlled human malaria infection. Strong Th1 cytokine responses induced by MVA ME-TRAP were associated with a skew in circulating T follicular helper cells towards a CXCR3+ phenotype and the observed reduction in antibody quantity and quality. This study illustrates that while a multistage-targeting vaccine strategy could provide high-level efficacy, the regimen design will require careful optimisation

Safety and immunogenicity of malaria vectored vaccines given with routine EPI vaccines in Gambian infants and neonates: a randomized controlled trial

Background: Heterologous prime-boost vaccination with ChAd63 and MVA encoding ME-TRAP has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Programme on Immunization (EPI) vaccines. Methods: We enrolled 65 Gambian infants and neonates, aged sixteen, eight or one week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events. Immunogenicity was evaluated using IFNγ ELISpot, whole‐blood flow cytometry and anti‐TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines. Results The vaccines were well tolerated in all age groups with no vaccine-related serious adverse events. High-level TRAP specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly. Conclusion: Malaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations. Trial registration The clinical trial was registered on Clinicaltrials.gov (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217).</p

Safety and immunogenicity of malaria vectored vaccines given with routine EPI vaccines in Gambian infants and neonates: a randomized controlled trial

Background: Heterologous prime-boost vaccination with ChAd63 and MVA encoding ME-TRAP has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Programme on Immunization (EPI) vaccines. Methods: We enrolled 65 Gambian infants and neonates, aged sixteen, eight or one week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events. Immunogenicity was evaluated using IFNγ ELISpot, whole‐blood flow cytometry and anti‐TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines. Results The vaccines were well tolerated in all age groups with no vaccine-related serious adverse events. High-level TRAP specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly. Conclusion: Malaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations. Trial registration The clinical trial was registered on Clinicaltrials.gov (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217).</p