Home Immunity Novel Prime and Spike Vaccine Strategy Leverages Existing Immunity Generated by Primary COVID-19 Vaccination

Novel Prime and Spike Vaccine Strategy Leverages Existing Immunity Generated by Primary COVID-19 Vaccination


Scientists at Yale University, USA, recently developed an intranasal spike-stimulating vaccine that induces robust mucosal immunity in the airways, in addition to boosting pre-existing systemic immunity generated by vaccination with mRNA. In partially immunized mice, the vaccine can completely prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The study is currently available on the bioRxiv* preprint server.

Study: Unadjuvanted intranasal vaccine booster elicits robust protective mucosal immunity against sarbecoviruses. Image Credit: Haris MM/Shutterstock


Currently approved vaccines against coronavirus disease 2019 (COVID-19), including mRNA-based and adenoviral vector-based vaccines, have shown over 85% efficacy in preventing SARS- CoV-2 and symptomatic COVID-19. These vaccines are also able to prevent viral transmission to some extent. However, some recent studies have shown that vaccine immunity may decline over time. The emergence of new viral variants is another potential cause of declining vaccine immunity.

Most COVID-19 vaccines are administered intramuscularly, which is very favorable for inducing potent systemic antibodies. However, this route of administration is not optimal for inducing adequate mucosal immunity at the site of infection, i.e. the respiratory tract. For complete prevention of viral transmission, strong mucosal immunity is necessary.

In the current study, scientists evaluated the immunogenicity and protective efficacy of a vaccination strategy that includes systemic priming with an mRNA-based COVID-19 vaccine (Pfizer/BioNTech) followed by stimulation intranasally with a SARS-CoV-2 spike protein without adjuvant.

Mucosal and systemic immunity

The SARS-CoV-2 spike protein used for intranasal stimulation was modified with a C-terminal T4 fibritin trimerization motif and proline and alanine substitutions in the furin cleavage site. These modifications were made to increase the stabilization and immunogenicity of the spike protein.

Mice were primed with the Pfizer vaccine intramuscularly, followed by an intranasal boost 14 days after the primary vaccination. Mucosal immune responses were assessed 7 or 14 days after booster vaccination.

The results revealed that the prime-spike vaccination scheme could induce potent mucosal and systemic anti-spike IgG and IgA antibodies in mice. Induction of binding antibody levels was significantly correlated with mucosal and systemic neutralizing titers. Moreover, the strong response of tissue-resident memory B cells induced by spike vaccination in the lungs. However, immunization with only a spike boost was insufficient to induce a robust antibody response.

Similar to humoral immunity, a strong induction of tissue-resident memory CD4+ and CD8+ T cells was observed in the lower and upper respiratory tract after primary vaccination. Importantly, the prime-spike vaccination given three months apart showed a similar ability to induce strong humoral and cellular immunity at both mucosal and systemic levels.

In addition to the recombinant spike protein without adjuvant, the immunogenicity of a spike protein encoding encapsulated polyplex mRNA was investigated in the study. The results revealed that polyplex-encapsulated spike booster vaccination could induce humoral and cellular immunity of similar intensity as spike booster vaccination without adjuvant.

Protection against severe SARS-CoV-2 infection

A low-dose primary vaccination schedule was used to mimic the decline in vaccine efficacy in the study. Mice immunized with the low-dose (prime) Pfizer vaccine received intranasal spiking without adjuvant or polyplex (boost) spiking 14 days after the primary vaccination. These mice were then challenged with wild-type SARS-CoV-2.

The results revealed that both boosting regimens could induce strong humoral and cellular immune responses in mice with suboptimal primary vaccination. Additionally, both booster regimens showed high protective efficacy against severe SARS-CoV-2 infection in terms of preventing body weight loss and mortality and reducing lung viral load and disease. .

The study also compared the immunogenicity of the prime–spike vaccination regimen with the Pfizer prime–Pfizer boost vaccination regimen. The results revealed that intranasal spike stimulation and intramuscular mRNA stimulation (Pfizer) can induce comparable immune responses in mice primed with the Pfizer vaccine.

Cross-reactive immunity

The effectiveness of the intranasal booster strategy in inducing cross-reactive immune responses was assessed in the study. To this end, mice primed with the Pfizer vaccine were intranasally administered a non-adjuvanted heterologous SARS-CoV spike protein. The results revealed that the tested prime-boost vaccination regimen is able to induce robust mucosal immunity against SARS-CoV spike as well as stimulate neutralizing antibodies against SARS-CoV-2 spike.

Significance of the study

The study describes the immunogenicity of a new vaccination strategy in which the Pfizer COVID-19 vaccine was used for the primary intramuscular immunization, and a SARS-CoV-2 spike without adjuvant was used for the immunization of intranasal recall. As highlighted in the study, this novel vaccination strategy can induce strong mucosal and systemic immunity in mice, which is sufficient to protect against lethal SARS-CoV-2 infection.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.