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

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


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

Most COVID-19 vaccines are administered intramuscularly, which is highly favorable for inducing strong 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 required.

In the current study, the scientists have evaluated the immunogenicity and protective efficacy of a vaccination strategy that includes systemic priming with mRNA-based COVID-19 vaccine (Pfizer/BioNTech) followed by intranasal boosting with unadjuvanted SARS-CoV-2 spike protein.

Mucosal and systemic immunity

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

The mice were primed with Pfizer vaccine intramuscularly, followed by intranasal spike boosting 14 days after the prime vaccination. Mucosal immune responses were assessed 7 or 14 days after booster vaccination.

The findings revealed that the prime–spike vaccination regimen could induce strong mucosal and systemic anti-spike IgG and IgA antibodies in mice. The induction in binding antibody levels significantly correlated with neutralizing titers at both mucosal and systemic levels. In addition, the prime–spike vaccination-induced strong tissue-resident memory B cell response in the lung. However, immunization with only spike booster was insufficient to induce a robust antibody response.  

Like humoral immunity, a strong induction of tissue-resident memory CD4+ and CD8+ T cells was observed in the lower and upper respiratory tract after prime–spike vaccination. Importantly, prime–spike vaccination administered at an interval of three months showed similar capability in inducing strong humoral and cellular immunity at both mucosal and systemic levels.

In addition to unadjuvanted recombinant spike protein, the immunogenicity of a polyplex-encapsulated mRNA encoding spike protein was investigated in the study. The findings revealed that the prime – polyplex-encapsulated spike boost vaccination could induce similar intensity humoral and cellular immunity as the prime – unadjuvanted spike boost vaccination.

Protection against severe SARS-CoV-2 infection

A low-dose prime vaccination regimen was used to mimic declining vaccine efficacy in the study. The mice immunized with low-dose Pfizer vaccine (prime) were intranasally administered with unadjuvanted-spike or polyplex-spike (boost) 14 days after prime vaccination. These mice were subsequently challenged with wild-type SARS-CoV-2.

The findings revealed that both booster regimens could induce strong humoral and cellular immune responses in mice with suboptimal prime vaccination. In addition, 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 pathologies.

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

Cross-reactive immunity

The efficacy of the intranasal boosting strategy in inducing cross-reactive immune responses was assessed in the study. For this purpose, mice primed with Pfizer vaccine were intranasally administered with unadjuvanted heterologous spike protein of SARS-CoV. The findings revealed that the tested prime-boost vaccination regimen is capable of inducing robust mucosal immunity against SARS-CoV spike as well as boosting neutralizing antibodies against SARS-CoV-2 spike.

Study significance

The study describes the immunogenicity of a novel vaccination strategy wherein Pfizer COVID-19 vaccine has been used for prime intramuscular immunization, and an unadjuvanted SARS-CoV-2 spike has been used for intranasal booster immunization. As evidenced 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 regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Mao, T. et al. (2022) "Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses". bioRxiv. doi: 10.1101/2022.01.24.477597.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Alanine, Antibodies, Antibody, B Cell, CD4, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Efficacy, immunity, Immunization, Mortality, Proline, Protein, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Weight Loss

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Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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