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 7

Pan-sarbecovirus DNA vaccines induce CD8+ T cell responses and partial protection against SARS-CoV-2 in K18-hACE2tg mice.

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Pan-sarbecovirus DNA vaccines induce CD8+ T cell responses and partial p...
(A) Schematic representation of the experiment. K18-hACE2tg mice (10 mice/group) were vaccinated intradermally with the indicated plasmid DNA vaccines thrice at 3-week intervals (days 0, 21, and 42). Mock-vaccinated animals served as negative controls. Nine days after the final vaccination (day 51), blood samples were collected to measure vaccine-specific CD8+ T cell responses. Three weeks after the final vaccination (day 63), the mice were challenged i.n. with a lethal dose of the Leiden-0008 SARS-CoV-2 isolate and BWs were measured daily as a parameter of disease. (B) CD8+ T cell responses in blood measured after 3 vaccinations (day 51) using H-2Kb tetramers containing ORF1ab nsp12-, M- (see Figure 3), or S-derived epitopes. In this experiment, CoVAX_MNS, but not CoVAX_ORF1ab, retained the C-terminal S reporter cassette; therefore, only CoVAX_MNS was able to induce responses to the S reporter epitope. Dots represent individual mice; bars and whiskers indicate means and SEM. These tetramer responses were evaluated by a Kruskal-Wallis test using Dunn’s multiple comparisons test. For multiplicity-adjusted P values: **P ≤ 0.01; ***P ≤ 0.002; ****P ≤ 0.0004. (C) BWs and survival of individual mice after SARS-CoV-2 challenge. Statistical analysis comparing the survival curves of vaccinated versus control mice by a log-rank (Mantel-Cox) test: for CoVAX_MNS, P = 0.06; for CoVAX_ORF1ab, P = 0.24.