Intranasal Boosting with Spike Fc-RBD of Wild-Type SARS-CoV-2 Induces Neutralizing Antibodies against Omicron Subvariants and Reduces Viral Load in the Nasal Turbinate of Mice

Abstract

The emergence of new immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and subvariants outpaces the development of vaccines specific against the dominant circulating strains. In terms of the only accepted immune correlate of protection, the inactivated whole-virion vaccine using wild-type SARS-CoV-2 spike induces a much lower serum neutralizing antibody titre against the Omicron subvariants. Since the inactivated vaccine given intramuscularly is one of the most commonly used coronavirus disease 2019 (COVID-19) vaccines in developing regions, we tested the hypothesis that intranasal boosting after intramuscular priming would provide a broader level of protection. Here, we showed that one or two intranasal boosts with the Fc-linked trimeric spike receptor-binding domain from wild-type SARS-CoV-2 can induce significantly higher serum neutralizing antibodies against wild-type SARS-CoV-2 and the Omicron subvariants, including BA.5.2 and XBB.1, with a lower titre in the bronchoalveolar lavage of vaccinated Balb/c mice than vaccination with four intramuscular doses of inactivated whole virion vaccine. The intranasally vaccinated K18-hACE2-transgenic mice also had a significantly lower nasal turbinate viral load, suggesting a better protection of the upper airway, which is the predilected site of infection by Omicron subvariants. This intramuscular priming and intranasal boosting approach that achieves broader cross-protection against Omicron variants and subvariants may lengthen the interval required for changing the vaccine immunogen from months to years.

HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration

“…Our previous studies have shown that subcutaneous or intramuscular immunization with HR121 protein in Freund's or aluminum adjuvant induces strong neutralizing antibodies that provide effective protection against SARS-CoV-2 infection in hACE2 mice, Syrian golden hamsters and rhesus macaques 13 . Recently, a large number of studies have demonstrated that intranasal delivery of SARS-CoV-2 vaccines with some appropriate adjuvants or viral vectors can promote mucosal immune responses 33 . Due to the immunogenicity of HR121, it may induce mucosal antibodies that neutralize its antiviral activity after multiple intranasal administration.…”

Autoantibodies against angiotensin‐converting enzyme 2 (ACE2) after COVID‐19 infection or vaccination

“…Active recombinant human ACE2 (Gln18‐Ser740) expressed in HEK293 cells was sourced commercially (ABclonal; Cat#: RP01277). In addition, we expressed human ACE2 (Ser19‐Arg708) in‐house using a baculovirus insect cell system as described previously 18 . Both commercial and in‐house ACE2 peptides were characterized using sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) and western blot analysis using a monoclonal antibody against ACE2 (R&D Systems; Cat#:AF933).…”

“…In addition, we expressed human ACE2 (Ser19-Arg708) in-house using a baculovirus insect cell system as described previously. 18 Both commercial and in-house ACE2 peptides were characterized using sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and western blot analysis using a monoclonal antibody against ACE2 (R&D Systems; Cat#:-AF933). Detailed protocols for in-house ACE2 expression and western blot analysis are described in the Supporting Information Material.…”

Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19

“…Intranasal vaccines offer the valuable benefit of inducing robust tissue-resident memory B and T cell responses within the respiratory system, thereby providing swift and potent primary defense against mucosal pathogens [ 102 , 103 ]. Cai et al [ 104 ] conducted a study that demonstrated the effectiveness of one or two intranasal boosts of the fragment crystallizable (Fc)-linked RBD-binding domain derived from the wild-type SARS-CoV-2 (Wuhan-Hu-1) in inducing significantly higher neutralizing antibodies against Omicron subvariants, including BA.5.2 and XBB.1. The combination of intramuscular priming and intranasal boosting can provide broader cross-protection against Omicron variants and subvariants, with the potential to prolong the interval needed for updating the vaccine immunogen from months to years [ 104 , 105 ].…”