Multiantigen pan-sarbecovirus DNA vaccines generate protective T cell immune responses
Jeroen van Bergen, Marcel G.M. Camps, Iris N. Pardieck, Dominique Veerkamp, Wing Yan Leung, Anouk A. Leijs, Sebenzile K. Myeni, Marjolein Kikkert, Ramon Arens, Gerben C. Zondag, Ferry Ossendorp
Jeroen van Bergen, Marcel G.M. Camps, Iris N. Pardieck, Dominique Veerkamp, Wing Yan Leung, Anouk A. Leijs, Sebenzile K. Myeni, Marjolein Kikkert, Ramon Arens, Gerben C. Zondag, Ferry Ossendorp
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Research Article COVID-19 Vaccines

Multiantigen pan-sarbecovirus DNA vaccines generate protective T cell immune responses

Abstract

SARS-CoV-2 is the third zoonotic coronavirus to cause a major outbreak in humans in recent years, and many more SARS-like coronaviruses with pandemic potential are circulating in several animal species. Vaccines inducing T cell immunity against broadly conserved viral antigens may protect against hospitalization and death caused by outbreaks of such viruses. We report the design and preclinical testing of 2 T cell–based pan-sarbecovirus vaccines, based on conserved regions within viral proteins of sarbecovirus isolates of human and other carrier animals, like bats and pangolins. One vaccine (CoVAX_ORF1ab) encoded antigens derived from nonstructural proteins, and the other (CoVAX_MNS) encoded antigens from structural proteins. Both multiantigen DNA vaccines contained a large set of antigens shared across sarbecoviruses and were rich in predicted and experimentally validated human T cell epitopes. In mice, the multiantigen vaccines generated both CD8+ and CD4+ T cell responses to shared epitopes. Upon encounter of full-length spike antigen, CoVAX_MNS-induced CD4+ T cells were responsible for accelerated CD8+ T cell and IgG Ab responses specific to the incoming spike, irrespective of its sarbecovirus origin. Finally, both vaccines elicited partial protection against a lethal SARS-CoV-2 challenge in human angiotensin-converting enzyme 2–transgenic mice. These results support clinical testing of these universal sarbecovirus vaccines for pandemic preparedness.

Authors

Jeroen van Bergen, Marcel G.M. Camps, Iris N. Pardieck, Dominique Veerkamp, Wing Yan Leung, Anouk A. Leijs, Sebenzile K. Myeni, Marjolein Kikkert, Ramon Arens, Gerben C. Zondag, Ferry Ossendorp

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Figure 6

CoVAX_MNS vaccination improves CD8+ T and B cell responses to multiple sarbecovirus S variants.

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CoVAX_MNS vaccination improves CD8+ T and B cell responses to multiple s...
(A) Schematic representation of the experiment. C57BL/6 mice (5 mice/group) were vaccinated intradermally with CoVAX_ORF1ab (1ab) or CoVAX_MNS (MNS) DNA vaccines, from which the reporter antigens had been removed (“norep” in Supplemental Table 5), 3 times at 3-week intervals (days 0, 21, and 42). Three weeks after the final vaccination (day 70), mice were challenged with full-length WT S from SARS-CoV-2 Omicron, SARS-CoV-2 Wuhan, or SARS-CoV-1, also by intradermal DNA injection. Eight days after exposure to these spikes (day 78), blood samples were analyzed for (B) CD8+ T cell responses to the H-2Kb–restricted S reporter antigen VNFNFNGL (absent from the vaccines, present in all 3 S DNAs) as well as (C) IgG1 and (D) IgG2c Ab responses to the different spikes. In the absence of an S challenge, CoVAX_MNS-vaccinated mice did not generate detectable S-specific CD8+ T cell (VNFNFNGL) or Ab (IgG, IgG2c) responses (data not shown). (E) Four weeks after exposure to full-length S (day 98), the specificity of these IgG responses was determined by testing the sera not only against the S to which the mice had been exposed (closed circles) but also against the other 2 spikes (open circles). Dots represent individual mice; bars and whiskers indicate means and SEM. Tetramer and Ab responses were evaluated by a 2-tailed Mann-Whitney (B–D) or Kruskal-Wallis test using Dunn’s multiple comparisons test (E). For multiplicity-adjusted P values: *P ≤ 0.05; **P ≤ 0.01.