Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the respiratory mucosa. We developed a vaccine strategy that we call “prime and spike,” which leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike). We show that prime and spike induces robust resident memory B and T cell responses, induces immunoglobulin A at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, prime and spike enables the induction of cross-reactive immunity against sarbecoviruses.

Abstract

Prime and Spike passes the sniff test

Nearly 2 years after COVID-19 vaccines became widely available, a combination of waning vaccine-induced immunity and unabated viral mutations have resulted in reduced vaccine effectiveness. Mao et al. developed an alternative vaccine-boosting strategy they call “prime and spike” in animal models of COVID-19. After primary vaccination with a messenger RNA vaccine (“prime”), animals received an intranasal dose of unadjuvanted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (“spike”). This approach resulted in robust cellular and antibody-based immunity in the mucosa that protected animals as strongly and durably as a parenteral boost while also blocking viral transmission better. Spike could be administered in a variety of formulations and, if derived from SARS-CoV-1, could offer strong cross-protection against both viruses. —STS

Abstract

An intranasal spike protein boost generates broadly protective anti-sarbecovirus mucosal immunity in animals.

Abstract

INTRODUCTION

During the first year of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple highly effective vaccines have been developed, using new technologies such as modified mRNA encapsulated in lipid nanoparticles and replication-deficient adenoviral vectors. Initial trials showed vaccine effectiveness >90% against symptomatic disease. Additional studies showed decreased infection rates of household contacts of vaccinated individuals, suggesting decreased rates of transmission. Unfortunately, waning immunity to vaccines and continued viral evolution with increasingly transmissible and immune-evasive variants have led to decreased vaccine effectiveness. Vaccines have also become much less effective at preventing transmission, which may be in part because of the poor induction of mucosal immunity within the respiratory tract.

RATIONALE

Although the goal of vaccination has been to prevent individual morbidity and mortality, the evolution of SARS-CoV-2 throughout the pandemic has highlighted the need for vaccines that better prevent transmission. Parenteral vaccines induce robust systemic immunity that is protective against disease. However, they induce poor immunity within the upper respiratory mucosa, where viral transmission occurs. Preclinical studies of both SARS-CoV-2 and influenza virus have demonstrated that intranasal vaccination decreases viral shedding and transmission relative to parenteral vaccines. Despite these studies, there is only one currently approved respiratory mucosal vaccine, FluMist, which is a live cold-adapted influenza virus. Most current clinical trials of mucosally administered SARS-CoV-2 vaccines rely on either replication-deficient or attenuated viral vectors, the safety and efficacy of which have yet to be established. All of these strategies become less effective with the development of antivector immunity. Here, we instead leverage preexisting immunity to boost mucosal immunity by intranasally administering unadjuvanted spike protein or mRNA. This consequently avoids the use of viral vectors or adjuvants in the respiratory tract.

RESULTS

We describe the preclinical development of an alternative vaccine strategy that we term “prime and spike” (P&S), which uses existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike booster. P&S elicits robust mucosal cellular and humoral memory responses, including the establishment of tissue-resident memory CD8 ⁺ T cells, CD4 ⁺ T cells, and B cells. Additionally, we found robust induction of mucosal immunoglobulin A (IgA) and IgG. Intranasal boosters can be delivered through distinct vaccine formulations, ranging from unadjuvanted trimeric recombinant spike proteins to spike-encoding mRNA encapsulated by immunosilent poly(amine-co-ester) (PACE) polymers. We found that an intranasal unadjuvanted spike booster can be administered months out from primary immunization and offers systemic neutralizing antibody responses comparable with that of mRNA–lipid nanoparticle (LNP) boost. P&S shows durability, leading to protection from lethal SCV2 challenge for as long as 118 days from vaccination. P&S is protective in hamsters and is superior to mRNA-LNP prime-boost at blocking transmission. Last, by using a divergent spike antigen from SARS-CoV-1, we demonstrate that P&S can generate mucosal immunity to SCV1 while also boosting systemic and mucosal neutralizing antibodies to SARS-CoV-2.

CONCLUSION

SARS-CoV-2 will continue to evolve and become more immune evasive and transmissible. We will require boosting in human populations for the foreseeable future. The respiratory mucosa provides a formidable barrier against viral pathogens after P&S administration. Therefore, strengthening mucosal immunity through vaccination holds substantial promise for enhancing protection and mitigating transmission. As new variants emerge, it will be a vital tool in combating other respiratory pathogens and the next pandemic.

A parenteral prime-unadjuvanted mucosal boost vaccine that elicits mucosal immunity against sarbecoviruses.

P&S converts systemic immunity generated by primary vaccination into local immunity in the respiratory mucosa. P&S affords protection against disease development, respiratory viral replication, and contact transmission after SARS-CoV-2 (SCV2) infection. Intranasal boosting by using a divergent spike protein from SARS-CoV-1 (SCV1) induces mucosal immunity against diverse sarbecovirus clades.