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 5

CoVAX_MNS-induced CD4+ T cell responses improve CD8+ T and B cell responses to full-length S.

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CoVAX_MNS-induced CD4+ T cell responses improve CD8+ T and B cell respon...
(A) Schematic representation of the S challenge experiment. C57BL/6 mice (5 mice/group) were vaccinated intradermally with mock (–), CoVAX_ORF1ab (ORF1ab), or CoVAX_MNS DNA vaccines, from which the reporter antigens had been removed (“norep” in Supplemental Table 5), on days 0, 3, 6, and 21. On day 46, CD4+ T cells were depleted, or not, by i.p. injection of CD4-specific Abs (αCD4), and 3 days later, mice were exposed to full-length WT SARS-CoV-2 (Omicron) S. To this end, mice were injected with DNA encoding S from SARS-CoV-2 Omicron VOC. (B) Eight days after exposure to these spikes, blood samples were analyzed for CD8+ T cell responses to the H-2Kb–restricted S reporter antigen VNFNFNGL (absent from the vaccines, present in full-length S) as well as (C) IgG and (D) IgG2c Ab responses to the SARS-CoV-2 Omicron spikes. As expected, 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). Dots represent individual mice; bars and whiskers indicate means and SEM. Tetramer (B) and Ab (C and D) responses were evaluated by 2-way ANOVA using Holm-Šídák multiple comparisons test. For multiplicity-adjusted P values: *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0004.