The ongoing spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses significant challenges to public health worldwide. The emergence of mutations and variants of concern (VOCs) has been a direct consequence of the virus's evolution under the selective pressure of antibody responses from recovered and/or vaccinated individuals. These mutations, particularly those in the virus's spike (S) protein, including the receptor-binding domain (RBD), can reduce the sensitivity to antibody neutralization and increase the virus's ability to bind to the angiotensin-converting enzyme 2 (ACE2) receptor in host cells, leading to higher transmissibility and infectivity.
The Rise of Omicron and Its Challenges
The Omicron variant, first identified in November 2021 in South Africa, spread rapidly across the globe. Its multitude of mutations in the S protein raised concerns about vaccine efficacy and antibody treatments. Omicron's original variant, B.1.1.529, included 37 mutations in the S glycoprotein, with 15 in the RBD. This VOC has evolved into several lineages, BA.1 through BA.5, and subsequent subvariants, posing significant challenges due to widespread re-infections and vaccine breakthrough infections (BTIs). Despite causing less severe symptoms than previous VOCs, Omicron has led to substantial hospitalizations and fatalities, especially among the unvaccinated.
The Shift Towards Upper Respiratory Tract Infections
Evidence suggests a shift in the Omicron variant's tendency towards the upper respiratory tract, facilitating easier virus release from the nose and mouth and increasing transmissibility. The presence of the virus in the upper respiratory tract, capable of eliciting a strong local mucosal immune response, may result in mild or asymptomatic infections. This highlights the potential of mucosal immunity for therapeutic or preventative purposes.
IgA Antibody Nasal Drops: A Novel Approach
A groundbreaking study published in the Proceedings of the National Academy of Sciences (PNAS) by researchers from the Karolinska Institute in Sweden has demonstrated that intramuscular mRNA and/or inactivated vaccines do not adequately enhance the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. The study introduced nasal drops containing IgA antibodies, which protected mice from SARS-CoV-2 infection. Dimeric and secretory IgA1 antibodies showed higher neutralizing activity against various VOCs compared to their IgG counterparts, partly due to increased affinity. The DXP-604 antibody, in its dimeric or secretory IgA1 form, significantly outperformed its IgG parent in neutralizing Omicron lineages BA.1, BA.2, and BA.4/5, with a 25 to 75-fold increase in immune activity. This suggests a new method for protecting at-risk populations from different SARS-CoV-2 variants and potentially other infections.
The Role of Secretory Immunoglobulin A (sIgA)
sIgA is the most abundant Ig type in secretions, playing a crucial role in mucosal defense and protection against respiratory virus infections. While serum IgA primarily exists as monomers (mIgA), sIgA consists of two IgA monomers linked by a joining (J) chain and associated with a secretory component (SC). dIgA, produced by B cells in the mucosa, is transported across the epithelium via the polymeric Ig receptor (pIgR). On the luminal side of the epithelium, pIgR is cleaved, leaving part of the SC attached, forming sIgA. IgA1 predominates in the upper respiratory tract, whereas IgA2 is more abundant in the lower gastrointestinal tract. During early infection, mucosal IgA dominates the neutralizing antibody response against SARS-CoV-2, with dIgA being more effective than IgG. Thus, delivering dIgA and sIgA via nasal spray could be the most effective and convenient option to block virus infection and enhance mucosal immunity against SARS-CoV-2.
Addressing Breakthrough Infections with Monoclonal IgA Antibodies
Given the high risk of breakthrough infections in individuals with insufficient mucosal IgA responses, researchers designed various forms of monoclonal IgA antibodies for direct application to mucosal surfaces. The dimerization of IgA significantly enhances the potency of the broadly neutralizing antibodies tested. Importantly, converting IgG to dimeric and secretory forms of IgA restored neutralizing capacity against the Omicron variant. Mice infected with the Omicron variant and treated with IgA antibodies via nasal administration showed significantly reduced viral loads in the trachea and lungs. IgA antibodies bound more strongly to the SARS-CoV-2 spike protein than the original IgG antibodies and were more effective in neutralizing the virus.
Fig 1. Intranasal administration of dimeric IgA in hACE2 mice is protective against Omicron BA.5.1
Mucosal Immunity and Vaccination Challenges
SARS-CoV-2 primarily infects the respiratory tract, making mucosal immunity crucial for protection. Most vaccines, however, focus on systemic immunity, with limited impact on mucosal sites. The study underscores the importance of enhancing mucosal immunity, suggesting that nasal vaccines or treatments could offer significant advantages for preventing and treating COVID-19 and future respiratory virus infections.
Conclusion
The research into nasal IgA antibody drops offers a promising avenue for enhancing protection against SARS-CoV-2, especially against the Omicron variant and its subvariants. By focusing on mucosal immunity and utilizing the unique properties of IgA antibodies, this approach may pave the way for more effective preventive measures and treatments for COVID-19 and potentially other respiratory infections.
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Reference
- Marcotte, Harold, et al. "Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages." Proceedings of the National Academy of Sciences 121.3 (2024): e2315354120.
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