Antigenic target, antibody subclass, function and glycans and SARS-CoV-2 coinfection impact the placental transfer of herpes simplex virus antibodies

ABSTRACT

Primary versus recurrent herpes simplex virus 1 or 2 (HSV-1 or HSV- 2) infection during pregnancy carries a higher risk of neonatal herpes suggesting that placental transfer of antibodies protects against transmission and infection. Murine and clinical studies demonstrate that antibody-dependent cellular cytotoxicity (ADCC) provides greater protection than neutralizing antibodies (nAbs) against disseminated neonatal disease. To quantify the relative transfer of HSV-specific Abs with different functions and targets and whether SARS-CoV-2 coinfection modified transfer, we conducted a prospective cohort study of mother-infant dyads prior to and during COVID-19. Total and HSV lysate, glycoprotein D (gD) and glycoprotein B (gB)- specific IgG, IgG1 and IgG3, nAbs, and ADCC were quantified in paired 3rd trimester maternal and cord blood. Transfer ratios (TR) were defined as cord maternal Ab levels. IgG1 and IgG3 subclass and gD or gB-specific Abs were isolated by column purification and glycan profiles were assessed using mass spectrometry. The pre-COVID study population included 21 term and 15 preterm dyads who were HSV-1 (± HSV-2) seropositive (+) enrolled between 2018-2019 and the peri- COVID cohort included 25 HSV-1 (±HSV-2)+term dyadswhosemothers were also SARS-CoV-2 PCR and COVID Ab+ at delivery;14 were asymptomatic and 11 had mild-moderate COVID disease. None of the mothers had active genital HSV lesions during delivery. HSV-specific IgG, IgG1, and IgG3 TR were higher in term compared to preterm pre-COVID dyads (all p< 0.05). Similarly, the neutralizing Ab TR was 2.4[1.5, 4.0] in term vs 0.8[0.6, 1] in preterm (median [95%CI], p< 0.0001) but the ADCC TR was < 1.0 for both groups. To determine if the low ADCC TR reflected antigenic target, subclass, and/or glycans, we enriched for anti-gD and anti-gB specific and IgG1 and IgG3 Abs. These envelope glycoproteins are primary targets of neutralizing and ADCC responses, respectively. The anti-gD Abs were exclusively IgG1 and had only neutralizing activity. In contrast, anti-gB Abs were both IgG1 and IgG3;the IgG1 gB Abs had both neutralizing and ADCC activity whereas the IgG3 were only neutralizing. The anti-gD Abs were enriched for glycans associated with an affinity for FcRn, whereas anti-gB Abs expressed glycans associated with both FcRn and FcγRIIIa (receptor-associated with ADCC activity) binding. There was no significant difference in HSV-specific IgG TR in pre-COVID vs COVID dyads (0.42) but the nAb TR was lower (p = 0.018) and ADCC TR higher (p<0.001) in COVID compared to pre-COVID patients. Studies are in progress to assess whether this reflects increased placental colocalization of FcRn and FcgRIIIA, which would favor the transfer of ADCCAbs or modified Fc glycans. ADCC Abs transfer relatively inefficiently compared to nAbs, particularly in preterm infants and this may contribute to an increased risk of HSV disease. ADCC Ab transfer increased with SARS-CoV-2 coinfection, which may reflect differences in glycans and/or alterations in the placental architecture. Defining the determinants of ADCC transfer has implications for future vaccine and monoclonal Ab strategies to prevent/treat neonatal herpes. We speculate that increasing the transfer of ADCC may be a key element in providing immune protection.