key: cord-0318191-897b33yr
authors: Plitman Mayo, R.; Raz, T.; Ben David, B.; Meir, G.; Barr, H.; solmesky, L.; Chen, R.; Idelson, A.; Zorzetti, L.; Gabbay-Benziv, R.; Yaffe Moshkovich, Y.; Biron-Shental, T.; Shechter-Maor, G.; Yitzhak Sela, H.; Glick, I.; Benyamini Raischer, H.; Salim, R.; Yogev, Y.; Beharier, O.; Goldman-Wohl, D.; Many, A.; Kovo, M.; Yagel, S.; Neeman, M.
title: Waning of the Humoral Response to SARS-CoV-2 in Pregnancy is Variant-Dependent
date: 2021-11-03
journal: nan
DOI: 10.1101/2021.11.03.21265478
sha: 86c435a686a07a76c8105b6604f0114254accf2d
doc_id: 318191
cord_uid: 897b33yr

Importance The SARS CoV2 alpha variant posed increased risk for COVID19 complications in pregnant women. However, its impact on the maternal humoral response and placental IgG transport remains unclear. Objective To characterize the maternal humoral waning and neonate immunity acquired during the third COVID19 wave in Israel, dominated by the Alpha variant, as compared to earlier Wildtype infections and humoral response to vaccination across gestation. Design Maternal and fetal blood serum were collected at delivery since April 2020 from parturients. Sera IgG and IgM titers were measured using the Milliplex MAP SARS CoV2 Antigen Panel supplemented with additional HA coupled microspheres. Setting A nationwide multicenter cohort study on SARS CoV2 infections and vaccination during pregnancy. Participants Expectant women presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 primary groups. 157 SARS CoV2 positive and 125 fully vaccinated during pregnancy, and 212 unvaccinated noninfected controls matched to the infected group by BMI, maternal age, comorbidities and gestational age. Eligibility criteria included pregnant women without active COVID19 disease, age over 18 years and willingness to provide informed consent. Main Outcomes and Measures Pregnant womens humoral response is dependent on the SARS CoV2 strain. Results The humoral response to infection as detected at birth, showed a gradual and significant decline as the interval between infection or vaccination and delivery increased. Significantly faster decay of antibody titers was found for infections occurring during the third wave compared to earlier infection or vaccination. Cord blood IgG antigens levels correlated with maternal IgG. However, cord IgG HA variance significantly differed in SARS CoV2 infections as compared to the other groups. No sexual dimorphism in IgG transfer was observed. Lastly, high fetal IgM response to SARS CoV2 was detected in 17 neonates, all showing elevated IgM to N suggesting exposure to SARS CoV2 antigens. Conclusions and Relevance Infections occurring during the third wave induced a faster decline in humoral response when compared to Wildtype infections or mRNA BNT162b2 vaccination during pregnancy, consistent with a shift in disease etiology and severity induced by the Alpha variant. Vaccination policies in previously infected pregnant women should consider the timing of exposure along pregnancy as well as the risk of infection to specific variants of concern.

Conclusions and Relevance: Infections occurring during the 3 rd wave induced a faster decline in humoral response when compared to Wildtype infections or mRNA BNT162b2 vaccination during pregnancy, consistent with a shift in disease etiology and severity induced by the Alpha variant.

Vaccination policies in previously infected pregnant women should consider the timing of exposure along pregnancy as well as the risk of infection to specific variants of concern.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Introduction SARS-CoV-2 variants of concern (VOC) associated with increased transmissibility, severity or possible immune evasion have rapidly dominated COVID-19 surges around the world 1 . Massive wholegenome SARS-CoV-2 sequencing as well as S gene target failures in PCR testing revealed the extremely rapid expansion of the alpha (B.1.1.7) lineage in the UK, consistent with its higher transmissibility, a 50% to 100% higher reproduction number, increased disease severity and increased mortality 2 . The Alpha variant has accumulated 23 mutations, of which 14 are non-synonymous and six synonymous 3-5 , involving changes in the S protein, in the receptor-binding domain (RBD), and in the nucleocapsid (N) 4 .

Of these changes 47% occurred in the gene encoding for the S protein, leading to alterations in the interaction with the human angiotensin-converting enzyme-2 (hACE2) receptor, thereby increasing the infection rate 3 . Consequently, the Alpha variant was the first to be designated as a VOC (2020/12/01) by Public Health England in the fall of 2020 6 .

In Israel, the 3 rd COVID-19 wave (2021/01/01 -2021/04/01) was dominated by the Alpha variant, while the earlier surges were dictated by the original SARS-CoV-2 virus 7 . Analysis of RT-PCR data from Israel revealed an increase of 40% in transmission for the alpha SARS-CoV-2 variant relative to the Wildtype strain 7 . This period coincided with the Israeli vaccination campaign, which included offering the Pfizer mRNA BNT162b2 vaccine to pregnant women due to the increasing evidence of severe and compromising COVID-19 complications during pregnancy 8, 9 , together with the indication that the Alpha variant poised increased severity and mortality for women relative to men 10 .

A recent study highlighted the fact that pregnant women have a reduced antibody response against SARS-CoV-2 when compared to non-pregnant women, with lower titers of IgG-S-RBD 11 .

Studies by us and others demonstrated the safety and benefits of vaccination during pregnancy, promoting its implementation for preventive maternal-fetal care 12, 13 . The humoral response to SARS-CoV-2 infection and vaccination in pregnancy showed that IgG efficiently crosses the placenta providing immunity for the newborn [13] [14] [15] [16] [17] [18] [19] . However, little is known about maternal and neonate IgG concentrations at term following early pregnancy infection or vaccination, as well as the impact of infection by VOC.

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The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint

In contrast to IgG, IgM antibodies do not cross the placental barrier thereby providing a sensitive measure for fetal exposure to viral antigens or the virus itself. Cases of cord IgM positivity following SARS-CoV-2 infection during pregnancy are relatively rare but have been reported by us and others 13, 19 , suggesting potential placental damage, exposure of the fetus to viral antigens, or in rare cases, vertical transmission 20 . As opposed to infection, no cord blood IgM for spike antigens has been detected among vaccinations 13 , consistent with no fetal exposure to antigens derived from the vaccine.

Herein, we report updated findings from the Israel Covid-19 in Pregnancy study 13 , concerning the evolution and dynamics of the maternal-fetal humoral response to SARS-CoV-2 infection and vaccination with the pandemic progression. Specifically, this work addresses for the first time the humoral response and waning of immunity for infection and vaccination during pregnancy, comparing the impact of the Wildtype versus Alpha variant dominated periods in Israel (2 nd versus 3 rd waves respectively).

Pregnant women admitted for delivery at eight medical centers in Israel (Hadassah Mount-Scopus, Wolfson, HaEmek, Hillel Yafe, Rabin, Shaare Zedek, Meir, and Sourasky Medical Centers) were approached for enrollment in the Israel Covid-19 in Pregnancy study, starting in April 2020. Eligibility criteria included maternal age ≥18 years and willing to provide informed consent. Pregnant women with active maternal COVID-19 disease were excluded from this study. The project cohort consisted of 1702 participants which were initially stratified into three main groups: 427 vaccine recipients (all collected between January to June 2021), 211 participants with past SARS-CoV-2 infection during pregnancy, and 1039 unvaccinated women without prior documentation for infection ( Figure 1a) .

Out of the 211 past SARS-CoV-2 positive participants, 139 maternal-fetal matched and 18 maternal only sera samples were included in the analyses (including 70 reported in our previous study 13 ).

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 1) . Overall, serology results were obtained for 494 Dyads: n=157 with past RT-PCR positive results, n=125 fully vaccinated and n=212 controls ( Figure   1a ). Participant clinical and neonate outcome characteristics are provided by study groups in Table 1 .

Maternal and cord serum samples were collected from the enrolled patients prior to delivery, and from the umbilical cord just following delivery, and handled as detailed in the Supplementary Material 13 .

Serum samples were prepared and analyzed using multiplexed fluorescent bead assay as previously described (details in Supplementary Material 13 ). Briefly, samples were thawed, heatinactivated at 56 o C for 30 minutes, and transferred to bar-coded 96-well plates for analysis. Serum IgG and IgM were detected using Milliplex MAP SARS-CoV-2 Antigen Panel 1 IgG (HC12SERG-85K) and

IgM (HC19SERM1-85K) supplemented with additional HA-coupled microspheres. Recombinant 6XHIS-HA protein derived from two isolates of influenza (Phuket /Singapore) were purchased from Immune Tech Corp and coupled to Bioplex Mag COOH beads according to manufacturer's instructions (Bio-Rad).

Coupling was confirmed by incubating with 1:1000 anti-HIS-PE (abcam) for 1 hour and washing 3 times with Milliplex wash buffer, with detection in a MAGPIX reader. Positive and negative controls were included in each analysis for accuracy and reproducibility.

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The copyright holder for this preprint this version posted November 3, 2021. IgG and IgM antibodies, as well as to test associations between time of exposure (i.e., to SARS-CoV-2 virus or to the Vaccine) and IgG and IgM concentrations. All statistical tests were based on two-tailed hypotheses. Differences were considered significant at P < 0.05.

Analysis of the study groups showed differences in maternal age, gravidity, parity and infant sex between the vaccinated and the control groups (Table 1) . Within the control group, 35 participants (16.5%) were found to be seropositive for N using IgG-N (mean net fluorescence intensity (MFI) > 1583) as the threshold 13 , which together with IgG seropositivity to the other SARS-CoV-2 antigens (S1, S2 and RBD), is indicative of induced immunity due to infection. Similarly, 17 vaccinated participants (13.6%) . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint were seropositive for IgG-N leading to an overall undiagnosed seropositivity rate of 15.43%. High fetal IgM response was defined as IgM-N > mean + 2SD (MFI > 741), and cord serum seropositivity was set for samples having a high IgM response for at least two antigens. Accordingly, 17 neonates (3.6 %): 7 from the control, 6 from the infected and 4 from the vaccinated groups were found to have a high IgM response ( Figure S1 ).

Maternal and cord serological response to SARS-CoV-2 infection were analyzed by trimester and wave of infection (Figure 2 and 3 , Table S1 and S2). The general AOV/AOCV test (Table S2) IgM-S1 and cord blood IgM-S1 were significantly lower at birth in women infected on the 1 st or 2 nd trimester, as compared to those infected in the 3 rd trimester (P<0.05). Similarly, maternal IgG for all antigens, IgM-S2 and IgM-N were significantly lower in women infected on the 2 nd trimester during the third wave, as compared to those infected in the 3 rd trimester (P<0.05). Furthermore, maternal MFI for all IgG antigens, IgM-S2 and IgM-N were significantly higher for 2 nd trimester infections during the 2 nd wave as compared to the 3 rd wave (P<0.05). Additionally, maternal IgM-S1 and IgM-RBD were significantly higher for 3 rd trimester infections during the 2 nd wave, as compared to 3 rd trimester infections during the 3 rd wave (P<0.05). Interestingly, cord IgM-S1 and IgM-S2 were significantly higher for 3 rd trimester infections during the 3 rd wave, as compared to infections during the 2 nd wave (P<0.05).

In the vaccinated group, the data were analyzed by the trimester of the first vaccine dose ( Figure   S2 , Table S3 ). MFI of maternal IgG-S1, IgG-RBD and IgM-S1 were significantly higher at birth for 3 rd trimester vaccination (P<0.05) as compared to 2 nd trimester vaccination.

The stability of maternal and fetal humoral protection induced by infection or vaccination was evaluated by analysis of the interval between exposure and delivery, thereby accounting for variation in . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint gestational age at delivery (Figure 3a) . Similar decay of antibody concentration was observed between vaccination and 2 nd wave infections (Figure 3b) . However, decay of maternal and fetal IgG for 3 rd wave infection was significantly faster than for 2 nd wave infection or vaccination (Figure 3b & 3c) .

IgG transfer ratio (TR) was calculated as cord divided by maternal MFI levels. TR of IgG-S1, IgG-S2 and IgG-RBD at delivery was significantly higher for 2 nd compared to 3 rd trimester vaccination.

Similarly, IgG-N TR was higher for 2 nd versus 3 rd trimester infections during the 2 nd wave (P<0.05).

Differences were also found between vaccinated and 2 nd wave infections for both 2 nd and 3 rd trimester exposure ( Figure S3 , Table S4 , P<0.05).

The impact of SARS-CoV-2 infections on the maternal-fetal IgG transfer was analyzed for equality of variances using three statistical tests (Table S5 ). The paired maternal-fetal serological responses are plotted by groups in Figure 4 , together with data density curves. The data shows no significant differences for maternal IgG-HA(Phuket) and IgG-HA(Singapore) MFI variances between the groups. Surprisingly, cord IgG-HA(Phuket) and IgG-HA(Singapore) MFI variances were significantly higher for 2 nd and 3 rd wave infections as compared to the vaccinated and control groups (Table S5) . On the other hand, maternal and cord SARS-CoV-2 antibody level variances differed only between the control and the remaining groups (Table S5) . No sexual dimorphism in IgG was observed for any of the measured parameters. Namely maternal and cord IgG levels were similar for male and female neonates ( Figure S4 )

Among the 476 cord samples tested, 17 samples were identified with a robust IgM response to at least three SARS-CoV-2 IgM antigens. Figure S5 highlights the 17 samples having high IgM response (big dots), which cluster in the top right corner when plotting IgM-RBD against IgM-N (second row, right column); it can be observed that contrary to the IgG response (top row), the IgM responses are independent from the maternal serological response (second row, left column). Additionally, the cord . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint serum positive samples showed also a high response to IgM-HA(Phuket) and IgM-HA(Singapore) (bottom row, right column).

Pregnant women have been at an increased risk of complications since the beginning of the coronavirus pandemic. Moreover, pregnant women have more severe infections and worse pregnancy outcomes for those infected during the SARS-CoV-2 Alpha variant dominated period compared to Wildtype infections and to non-pregnant women 21 , but also have reduced IgG-S-RBD titers as compared to non-pregnant women 11 . We report here for the first time that the maternal humoral response to SARS-CoV-2 during the Alpha variant dominated period is significantly weaker when compared to infections during the Wildtype virus dominated wave. These findings suggest that the SARS-CoV-2 Alpha variant is less immunogenic, and perhaps can partially evade the immune system of pregnant women.

Cord serum anti-SARS-CoV-2 IgG concentrations were similar for infections in the 2 nd and 3 rd waves, indicating that the transfer of immunity to the developing fetus is less sensitive to waning of maternal IgG and less susceptible to SARS-CoV-2 mutations. These results highlight the importance of placental regulation and active transport for fetal immunity. Interestingly, the variance of cord serum IgG-HA(Phuket) and IgG-HA(Singapore) concentrations was significantly higher for the PCR-positive group relative to control and vaccinated despite the fact that variances among maternal levels were similar.

These results implicate SARS-CoV-2 infection during pregnancy in disruption of placenta IgG, resulting in a decreased neonate immunity against Influenza. This is is consistent with recent reports of placental SARS-CoV-2 infections and damage [22] [23] [24] . Lastly, in contrast to a recent study of a smaller cohort 25 , we show here that cord IgG levels were similar for male and female neonates.

The decline of antibody titers following infection attracted much of attention because of the emergence of several variants of concern and since it serves as the basis for vaccination policies in previously infected or vaccinated individuals 26 . A recent study showed that the decay rates for IgG-RBD-S in the general population were not significantly different between SARS-CoV-2 infection and . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint vaccination, and that antibody titers were still detectable 6 months after exposure to antigens 26 . Our data shows that in pregnant women the antibody decay rate is also similar for vaccinated and for infections during the 2 nd wave, dominated by the Wildtype variant. However, the decay rate was significantly faster for 3 rd wave infections. Together with the lower antibody titers found for infections during the Alpha variant dominated period, this study demonstrates that pregnant women mount a weaker and shorter immune response against SARS-CoV-2 Alpha variant compared to Wildtype infections.

Clinically, the results reported here underscore for the importance of vaccinating pregnant women, who were infected prior to pregnancy or during early stages of pregnancy, particularly with the SARS-CoV-2 alpha variant. Due to the rapid decay of antibodies, these women might be at increased risk for re-infection. Our understanding on the decline of mRNA BNT162b2 vaccine induced antibody titers across gestation remains poor. Evidence is needed to support policies of immunity boosting during the pre-natal period. In the present study, we demonstrate that following vaccination, there is a mild decline in maternal antibody titers across gestation, but not in cord serum antibody levels, supporting the efficiency of vaccination during pregnancy for neonate immunity. Therefore, vaccination during the second trimester provides defense to both mother and fetus. Interestingly, a high IgG transfer ratio was found for first trimester wave 2 infections indicating that infection in the early stages of pregnancy also leads to sustained fetal immunity.

Transplacental IgG transfer is mediated by FcRn, found in the fetal endothelium and within the syncytiotrophoblast layer, which is in direct contact with maternal blood. Ex vivo models have demonstrated that IgG bound to viral antigens can be transported to fetal blood 27 , potentially triggering a fetal immune response. It is well known that there is no transport of IgM across the placenta; however, fetal IgM has been detected in fetal blood from about 13 weeks of gestation 28 . Therefore, high fetal IgM concentrations may suggest an intrauterine infection or immunological stimulation 29-31 by viral antigens transported bound to IgG 27 or cross reactivity of low affinity fetal IgM . Cases of possible vertical SARS-CoV-2 transmission are rare, but have been previously reported 13, 20, 32 . Hence, the robust IgM response to all SARS-CoV-2 antigens found in seventeen neonates could be a result of immunological stimulation . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint and not necessarily a vertical transmission of the SARS-CoV-2 virus. The elevation of IgM for HA in these neonates is consistent with transplacental antigen presentation or placental dysfunction.

The present work possesses several limitations, including bias in sample collection due to daytime recruitment of participants, thereby excluding most emergency cases. The period of sample collection differed among groups, as the Israeli vaccination campaign started after the commencement of the study. Additionally, antibody levels were quantified using antigens of the original virus, and may thus show reduced affinity to antibodies induced by the alpha variant.

Pregnancy induces particular changes in a women's immune system placing them at a vulnerable position when it comes to infections. Therefore, general population immunity dynamics are not always applicable to pregnant women. This is the first study to compare the evolution and dynamics of the maternal-fetal humoral response between Alpha variant and Wildtype SARS-CoV-2 infections, demonstrating that pregnant women response is variant dependent. Additionally, this work enhances the important role of active transport and placental regulation for fetal immunity supporting vaccination during pregnancy.

This work was supported by an Israeli Science Foundation KillCorona grant 3777/19 (to MN, MK, SY, AM) and by a research grant from the Weizmann Institute Fondazione Henry Krenter (to MN). We would like to thank the patients who made this research possible.

The authors have declared that no conflict of interest exists.

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The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint Tables and Figure Legends   Table 1 : Clinical parameters of the study groups.

Clinical parameters of the study groups. The control sub-group was matched to the SARS-CoV-2 positive group based on maternal age, gestational age, BMI, gravidity, parity and maternal comorbidities. a,b

Values without a common superscript and within a row differed between the study groups (P < 0.01). Supplementary Table S5. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 3, 2021. Pregravid BMI (Kg/ ! ), mean ± SD Birthweight, mean ± SD, grams 4 (5.8) 6 (4.9) 11 (6.5) NICU, n(%) -26.3 ± 8.3 -PCR-positivity GA, mean ± SD, weeks . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint

First vaccine dose GA, mean ± SD, weeks Continuous parameters were analyzed by Kruskal-Wallis one-way ANOVA test, following by Dunn's allwithin a,b pare proportional data. square analysis was used to com -sons tests; Pearson Chi pairwise compari a row, values without a common superscript significantly differed (P < 0.05). * within a row marks differences in the recruited groups.

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The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint Figure 1 . Study Design . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted November 3, 2021. ; https://doi.org/10.1101/2021.11.03.21265478 doi: medRxiv preprint Figure 3 . SARS-CoV-2 IgG Antibody Level Waning Across Gestation . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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