Trivalent NDV-HXP-S vaccine protects against phylogenetically distant SARS-CoV-2 variants of concern in mice

Abstract

Equitable access to vaccines is necessary to limit the global impact of the coronavirus disease 2019 (COVID-19) pandemic and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In previous studies, we described the development of a low-cost vaccine based on a Newcastle Disease virus (NDV) expressing the prefusion stabilized spike protein from SARS-CoV-2, named NDV-HXP-S. Here, we present the development of next-generation NDV-HXP-S variant vaccines, which express the stabilized spike protein of the Beta, Gamma and Delta variants of concerns (VOC). Combinations of variant vaccines in bivalent, trivalent and tetravalent formulations were tested for immunogenicity and protection in mice. We show that the trivalent preparation, composed of the ancestral Wuhan, Beta and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant.

Monovalent and trivalent VSV-based COVID-19 vaccines elicit potent neutralizing antibodies and immunodominant CD8+ T cells against diverse SARS-CoV-2 variants

“…The novel rVSV-Beta and rVSV-Delta vaccines generated nAbs against SARS-CoV-2 Wuhan_USAWA1 , however rVSV-Beta/Beta prime-boost immunization was ineffective at neutralizing matched SARS-CoV-2 Beta and more mutated variants. Other studies which tested monovalent Beta vaccines, in the Newcastle Disease Viral vector or mRNA vaccine platform, showed neutralization of SARS-CoV-2 B.1.351 (19,20). Expression of Beta spike was confirmed in our rVSV-Beta vaccine, however the lack of nAbs generated after immunization may be due to sequence differences between the immunizing rVSV-Beta vaccine spike, which lacked modifications (L18F, D80A and Del 242-244) located outside of the RBD, when compared to the SARS-CoV-2 Beta used in this study.…”

“…In all these studies, and ours, the contribution of each variant spike to the immune response is not clear. One study tested for the differential IgG detection of variant spikes with immune sera induced following monovalent and multivalent immunization of animals, showing induction of broad and consistent antibody cross-reactivity across all vaccine regimens (20), failing to decipher the contribution of each spike to the immune response. Our rVSV-Trivalent prime-boost vaccine regimen provided high, consistent, and broad neutralization of all variants tested, from SARS-CoV-2 Wuhan_USAWA1 to the most recent variant of concern, SARS-CoV-2 Omicron .…”

“…This is different from other studies where the BriLife® rVSV vaccine exhibited reduced effectiveness against SARS-CoV-2 B.1.529 versus the original SARS-CoV-2 virus, notably this vaccine had spontaneously acquired mutations evident in some SARS-CoV-2 variants (10). Moreover, the Newcastle-based monovalent Wuhan spike vaccine did not neutralize Omicron, but neutralization was achieved with trivalent and tetravalent formulations (20). The effectiveness of our vaccines against SARS-CoV-2 Omicron suggests inherent advantages of the rVSV vaccine platform.…”

“…Our rVSV-Trivalent vaccine was formulated to test whether the presence of multiple, varied spike sequences in a vaccine would induce cross-protective immune responses against unmatched and distinct emerging lineages of SARS-CoV-2. This approach has been utilized with multiple vaccine platforms against SARS-CoV-2 (19)(20)(21). Bivalent mRNA boosters developed combining Wuhan and Beta sequences, showed effective neutralization of SARS-CoV-2 B.1.612.7 and SARS-CoV-2 B.1.529 at day 29 post-boost (19), with a response detectable at day 181, albeit neutralizing titers were less against SARS-CoV-2 B.1.529 when compared to SARS-CoV-2 B.1.617.2 (19).…”

“…Bivalent mRNA boosters developed combining Wuhan and Beta sequences, showed effective neutralization of SARS-CoV-2 B.1.612.7 and SARS-CoV-2 B.1.529 at day 29 post-boost (19), with a response detectable at day 181, albeit neutralizing titers were less against SARS-CoV-2 B.1.529 when compared to SARS-CoV-2 B.1.617.2 (19). Multivalent vaccines using the Newcastle virus as the vaccine vector have tested trivalent (Wuhan, Beta, Delta) and tetravalent (Wuhan, Beta, Delta, Gamma) formulas, with an increase to four different spike variants in the tetravalent exhibiting only a modest increase in nAb titer that did not translate to increased protection following challenge with SARS-CoV-2 Wuhan, Delta or Mu viruses (20). In all these studies, and ours, the contribution of each variant spike to the immune response is not clear.…”