Cross-protective antibodies against common endemic respiratory viruses

Abstract

Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, the elderly, and those with underlying lung disease. A protective monoclonal antibody exists for RSV, but clinical use is limited to high-risk infant populations. Hence, therapeutic options for these viruses in vulnerable patient populations are currently limited. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3 × 1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens at 3.62 Å resolution for 3 × 1 bound to HPIV3 and at 2.24 Å for MxR bound to RSV, providing a structural basis for in vitro binding and neutralization. Together, a cocktail of 3 × 1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.

A neutralizing antibody potently prevents RSV A and B infections by targeting a conserved region of the prefusion F

“…However, low-dose palivizumab offered limited protection, reducing viral loads by approximately 20-fold in the lungs and 4fold in nasal turbinates (Fig. 6a), echoing earlier ndings 33,48 . Pulmonary histopathology implied that h5B11 was more adept at curtailing pulmonary in ammation than nirsevimab, particularly in lessening alveolitis and interstitial pneumonitis (Fig.…”

“…1e-h). Comparatively, nirsevimab, which has been proved display approximately 4-fold enhanced in vitro neutralizing activity over its precursor D25 against B18537 21,33,35,42 . We found that nirsevimab could effectively neutralize A2, Long and B9320, with comparable potencies (IC 50 : 1.79-4.61 ng/mL) to that of 5B11.…”

“…1). Furthermore, D25 was also reported with weaker neutralizing potency against several RSV-B strains, including B18537 [33][34][35][36] . To explore the underlying mechanism behind the reduced in vivo prevention of nirsevimab against B18537 infection, we initially assessed its binding to the pre-F and post-F proteins from strain A2 and B18537, respectively, via ELISA, nding signi cantly weaker binding to B18537 pre-F compared to A2 pre-F (Fig.…”

“…Nonetheless, the targeted antigenic site Ø's low conservation raise concerns about potential immune evasion 30,31 , as evidenced by the identi cation of two nirsevimab-resistant RSV strains with residue substitutions at site Ø in phase trial 32 . Furthermore, some RSV B strains, for instance, B18537, exhibit resistance to nirsevimab's precursor, D25 [33][34][35][36] . Recent ndings also highlight a discrepancy between in vitro and in vivo e cacies of nirsevimab 37 .…”

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses

“…While IgA bnAbs have been described for antigenically distinct viruses that infect mucosal surfaces such as HIV [ 83 , 107 ], SARS-CoV-2 [ 85 ], and common respiratory viruses [ 108 ], to our knowledge, F25.S02 is the first known IgA bnAb against flaviviruses. A recent study showed that infection by the malaria parasite, Plasmodium falciparum , another mosquito-borne pathogen, induces serum IgA production in humans that contribute to protection against disease [ 109 ].…”