Boosting of SARS-CoV-2 immunity in nonhuman primates using an oral rhabdoviral vaccine

Abstract

An orally active vaccine capable of boosting SARS-CoV-2 immune responses in previously infected or vaccinated individuals would help efforts to achieve and sustain herd immunity. Unlike mRNA-loaded lipid nanoparticles and recombinant replication-defective adenoviruses, replicating vesicular stomatitis viruses with SARS-CoV-2 spike glycoproteins (VSV-SARS2) were poorly immunogenic after intramuscular administration in clinical trials. Here, by G protein trans-complementation, we generated VSV-SARS2(+G) virions with expanded target cell tropism. Compared to parental VSV-SARS2, G-supplemented viruses were orally active in virus-naive and vaccine-primed cynomolgus macaques, powerfully boosting SARS-CoV-2 neutralizing antibody titers. Clinical testing of this oral VSV-SARS2(+G) vaccine is planned.

Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior protective humoral immune response to SARS-CoV-2

“…32,35 Recently, VSV-vectored spike antigen that was administered via the oral route efficiently boosted the immune response to SARS-CoV-2 in nonhuman primates. 36 In summary, our findings demonstrate that trans-complementation of VSV-vectored vaccines with the VSV G protein has multiple impacts: (1) it improves virus yield to maximize vaccine production, (2) it allows efficient ACE2-independent intramuscular immunization leading to dramatically enhanced immune responses even after a single administration, (3) it supports the induction of broadly neutralizing antibodies when associated with the proper antigen. Future development of VSV-vectored vaccines will include improved induction of protective immune responses against conserved epitopes and enhanced mucosal immunity.…”

“…32, 35 Recently, VSV-vectored spike antigen that was administered via the oral route efficiently boosted the immune response to SARS-CoV-2 in nonhuman primates. 36…”

Preclinical immunogenicity and efficacy of a candidate COVID-19 vaccine based on a vesicular stomatitis virus-SARS-CoV-2 chimera

“…The hypothesis that skeletal muscle is not an effective site for Spike-dependent VSV∆G-SARS-CoV-2 replication also has been discussed by others based on their research with similar chimeric viruses. 50 , 86 , 94 Thus, although the VSV∆G-SARS-CoV-2 particles displaying Spike arrays might be quite immunogenic after IM injection in rodents in the absence of significant infection and replication, it is conceivable that a similar quantity of virion particles injected a single time into a much larger macaque 94 or human muscle 18 would be less immunostimulatory in the absence of a potent adjuvant, administration of a booster dose, 95 or immune system priming, for example, by previous infection with SARS-CoV-2. 18 …”

“… 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 Consistent with this explanation, it also is clear that VSV vectors encoding Spike immunogens are immunogenic by other vaccination routes if they are designed to use infection pathways that are independent of ACE2. 27 , 50 , 94 , 96 , 97 , 98 , 99 Our initial hamster study using alternative routes assessed two mucosal vaccination methods. The high volume IN/OM combination was used initially to enable infection across multiple mucosal surfaces in the upper respiratory tract ( Figure 5 a), whereas another group was vaccinated by applying virus only to OM surfaces because data were emerging on ACE2 abundance and the susceptibility of cells to SAR-CoV-2 infection in the oral cavity.…”

Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior immune response to SARS-CoV-2

“…In contrast to the presently approved mRNA vaccines, which rely on intramuscular administration, there is already first evidence from the hamster model that mucosally applied VSV-vectored COVID-19 vaccines can in principle be very effective in preventing virus shedding from the respiratory tract 32 , 35 . Recently, VSV-vectored spike antigen that was administered via the oral route efficiently boosted the immune response to SARS-CoV-2 in nonhuman primates 36 .…”