Pan-neutralizing, germline-encoded antibodies against SARS-CoV-2: Addressing the long-term problem of escape variants

Abstract

Despite the initially reported high efficacy of vaccines directed against ancestral SARS-CoV-2, repeated infections in both unvaccinated and vaccinated populations remain a major global health challenge. Because of mutation-mediated immune escape by variants-of-concern (VOC), approved neutralizing antibodies (neutAbs) effective against the original strains have been rendered non-protective. Identification and characterization of mutation-independent pan-neutralizing antibody responses are therefore essential for controlling the pandemic. Here, we characterize and discuss the origins of SARS-CoV-2 neutAbs, arising from either natural infection or following vaccination. In our study, neutAbs in COVID-19 patients were detected using the combination of two lateral flow immunoassay (LFIA) tests, corroborated by plaque reduction neutralization testing (PRNT). A point-of-care neutAb LFIA, NeutraXpress™, was validated using serum samples from historical pre-COVID-19 negative controls, patients infected with other respiratory pathogens, and PCR-confirmed COVID-19 patients. Surprisingly, potent neutAb activity was mainly noted in patients generating both IgM and IgG against the Spike receptor-binding domain (RBD), in contrast to samples possessing anti-RBD IgG alone. We propose that low-affinity, high-avidity, germline-encoded natural IgM and subsequent generation of class-switched IgG may have an underappreciated role in cross-protection, potentially offsetting immune escape by SARS-CoV-2 variants. We suggest Reverse Vaccinology 3.0 to further exploit this innate-like defense mechanism. Our proposition has potential implications for immunogen design, and provides strategies to elicit pan-neutAbs from natural B1-like cells. Refinements in future immunization protocols might further boost long-term cross-protection, even at the mucosal level, against clinical manifestations of COVID-19.

Seroprevalence and durability of antibody responses to AstraZeneca vaccination in Ugandans with prior mild or asymptomatic COVID-19: implications for vaccine policy

“…In contrast, after priming, peak levels of S-IgM antibodies were significantly lower at 19.46 (CI 19.43–19.49) BAU/mL, declined rapidly, and remained low for the more significant part of the 12-month study period. These data agree with the more extended durability of IgG and IgA relative to IgM antibodies ( 4 ), and the vaccine-induced expansion of S-IgG and IgA levels ( 5 , 30 ) demonstrated by other vaccines. In contrast, the Oxford-AstraZeneca vaccine elicited a more rapid immune response in this cohort than in two African studies ( 29 , 31 ), but agreed with an Israeli study where the peak occurred before three weeks ( 32 ).…”

“…After the initial IgM response, which declines relatively rapidly with viral clearance, class-switched antibodies, predominantly IgG and IgA, are produced ( 3 ). These class-switched antibodies are responsible for the protective long-term memory responses against SARS-CoV-2 ( 4 , 5 ), which enables the body to respond rapidly when re-exposed to an infection. Quantifying the levels of circulating class-switched B cell responses is critical for assessing the state of population-wide immunity and informing strategies for boosting immunity.…”

Understanding the biosynthesis of human IgM SAM-6 through a combinatorial expression of mutant subunits that affect product assembly and secretion

“…These natural IgMs play critical functions in immune surveillance [4,5]. The potential values of the IgM class for human therapeutics and diagnostic tools were re-recognized during the recent SARS-Cov-2 pandemic because the high mutation rate of surface glycoprotein and the concomitant generation of escape mutants was a significant concern for the antibody-based neutralization strategy using IgGs [6][7][8].…”

Understanding the biosynthesis of human IgMs through a combinatorial expression of mutant subunits that affect different assembly steps

“…These natural IgMs play critical functions in immune surveillance by virtue of their low affinity target binding and poly-reactivity [4,5]. The values of the IgM class for human therapeutics and diagnostic tools were recently re-recognized during the SARS-Cov-2 pandemic because the high mutation rate of surface glycoprotein and the concomitant generation of escape mutants was a significant concern for the antibody-based neutralization strategy using IgGs [6][7][8].…”

“…The copyright holder for this preprint this version posted September 5, 2023. ; https://doi.org/10.1101/2023.09.01.555973 doi: bioRxiv preprint generation of escape mutants was a significant concern for the antibody-based neutralization strategy using IgGs [6][7][8].…”