Intranasal administration of a single dose of MVA-based vaccine candidates against COVID-19 induced local and systemic immune responses and protects mice from a lethal SARS-CoV-2 infection

Abstract

Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4+ and cytotoxic CD8+ T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.

Defending against SARS-CoV-2: The T cell perspective

“…The viral control was observed in the absence of neutralizing antibodies, and it was linked to the induction of specific CD8+ T cell responses (183). Finally, intranasal immunization has been shown to provide protection against VoCs in animal models (243,244). These data highlight both the protective value of SARS-CoV-2-specific T cells resident in the upper respiratory tract and the effective nextgeneration COVID-19 intranasal vaccine approach to induce mucosal immunity against current and future VoCs, which could be a promising strategy to reduce breakthrough infections and curb SARS-CoV-2 transmission.…”

Recent developments in the immunopathology of COVID‐19

“…Recently, a diversity of animal experiments and clinical trials are ongoing to evaluate the immune responses and the safety and efficacy of intranasal administration of COVID-19 vaccines, respectively. 220 It is hypothesized that intranasal vaccination may induce both mucosal and systemic immune responses, 221 and thus the…”

“…It is hypothesized that intranasal vaccination may induce both mucosal and systemic immune responses, 221 and thus the local mucosal immunity may prevent the virus infection through the upper respiratory tract and block transmission to other people 222 . In mice, intranasal administration of virus‐based vaccine candidates expression SARS‐CoV‐2 spike protein elicited robust specific IgG and IgA antibodies and polyfunctional S‐specific Th1‐skewed CD4 + and cytotoxic CD8 + T‐cell immune responses 221 . Four COVID‐19 mucosal vaccines have been approved as booster for the prevention of COVID‐19 infection in China, Russia, India and Iran 222 .…”

Enhanced Protection from SARS-CoV-2 Variants by MVA-Based Vaccines Expressing Matched or Mismatched S Proteins Administered Intranasally to hACE2 Mice

“…We and others described animal studies supporting use of the host-range restricted vaccinia virus Ankara (MVA) as an alternative vector for COVID-19 vaccines 12–16 . Recent animal studies demonstrated advantages of IN delivery of recombinant MVAs (rMVAs) expressing S 17–19 . Anti-SARS-CoV-2 IgA and IgG as well as specific T cells were detected in the lungs of IN vaccinated mice and virus was diminished in the upper and lower respiratory tracts following challenge of K18-hACE2 mice with SARS-CoV-2.…”

“…We and others described animal studies supporting use of the host-range restricted vaccinia virus Ankara (MVA) as an alternative vector for COVID-19 vaccines [12][13][14][15][16] . Recent animal studies demonstrated advantages of IN delivery of recombinant MVAs (rMVAs) expressing S [17][18][19] .…”