Combining Liver- and Blood-Stage Malaria Viral-Vectored Vaccines: Investigating Mechanisms of CD8+ T Cell Interference

Abstract

Replication-deficient adenovirus and modified vaccinia virus Ankara (MVA) vectors expressing single pre-erythrocytic or blood-stage Plasmodium falciparum antigens have entered clinical testing using a heterologous prime-boost immunization approach. Here we investigated the utility of the same immunization regime when combining viral vectored vaccines expressing the 42kDa C-terminus of the blood-stage antigen merozoite surface protein 1 (MSP142) and the pre-erythrocytic antigen circumsporozoite protein (CSP) in the P. yoelii mouse model. We find that vaccine co-administration leads to maintained antibody responses and efficacy against blood-stage infection, but reduced secondary CD8+ T cell responses against both antigens and efficacy against liver-stage infection. CD8+ T cell interference can be minimized by co-administering the MVA vaccines at separate sites, resulting in enhanced liver-stage efficacy in mice immunized against both antigens compared to just one. CD8+ T cell interference (following MVA co-administration as a mixture) may partly be caused by a lack of physiological space for high magnitude responses against multiple antigens, but is not caused by competition for presentation of antigen on MHC class I molecules, nor is it due to restricted T cell access to APCs presenting both antigens. Instead, enhanced killing of peptide-pulsed cells is observed in mice possessing pre-existing T cells against two antigens, in comparison to just one, suggesting priming against multiple antigens may in part reduce the potency of multi-antigen MVA vectors to stimulate secondary CD8+ T cell responses. These data have important implications for the development of a multi-stage or multi-component viral vectored malaria vaccine for use in humans.

Baculovirus-Vectored Multistage Plasmodium vivax Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites

“…However, a major concern for the development of multivalent vaccines is the potential for vaccine interference which would be associated with poor immune responses (35). In fact, it has been reported that immune responses to the individual components of multiantigen malaria vaccines can potentially be suppressed by immune interference (36)(37)(38)(39)(40)(41)(42)(43). The BDES-Pvs25-PvCSP-G vaccine successfully induced high Pvs25-, PvCSP(Sal)-, and PvCSP(PNG) repeatspecific Ab titers, suggesting an absence of immune interference.…”

A Hybrid Multistage Protein Vaccine Induces Protective Immunity against Murine Malaria

“…A major concern for the development of multivalent vaccines is the potential for vaccine interference that would be associated with poor immune response (29). This effect has been reported using combinations of recombinant proteins (PyMSP-1 42 and PyMSP-8 [25] or PfMSP-1 42 and PfAMA-1 [17]) or using viral vectors combining PyCSP and PyMSP-1 42 (13). In these models, reduced antibody or CD8 ϩ T cell responses suggest a potential adverse interaction that would preclude the use of MSP-1 as a component of a multiantigen vaccine (25).…”

Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge

“…However, no significant difference in ELISpot responses was observed between mice vaccinated with ChAdOx1 NP+M1 or a combination of ChAdOx1 NP+M1 and ChAdOx1-H7, administered into separate limbs. This approach has previously been shown to augment immune responses and avoid competition between two vaccines administered together (12).…”

“…However, delivery of multiple antigens can result in immune competition (38,39), which can be largely circumvented by administration of the viral-vectored vaccine encoded antigens to separate sites as described here. While the exact mechanisms of antigenic interference following vaccination remains unknown, this phenomenon is thought to be influenced by spatial constraints on T cells (40,41).…”

“…Viral-vectored vaccines have been developed for the induction of strong humoral and potent cellular immunity toward encoded antigens. An added strength of this platform is that viral vectors can accommodate more than one antigen (12). For heterologous prime-boost vaccination strategies, typically, one viral vector (e.g.…”