Antibodies to SARS-CoV-2 in follicular fluids and their association with assisted reproduction

Abstract

Introduction: Every second woman suffering from infertility asks for medical help. There is public concern that vaccination-induced antibodies (Ab) are negatively associated with fertility. A recent study has demonstrated an association between SARS-CoV-2 vaccination and a lower pregnancy rate in the subsequent 60 days. Consequently, Ab could affect fertility success in assisted reproduction.

Methods: To address this question, we compared fertilization outcomes of vaccinated (n=35) and nonvaccinated (n=34) women. Paired serum samples and multiple follicular fluids (FF) (up to 10 from the same donor) were collected during the course of assisted reproduction and characterized for oocyte quality, the presence of Ab and trace element concentrations.

Results: The results showed a positive correlation of vaccination-induced neutralizing activity of SARS-CoV-2-Ab in serum and FF. On average, Ab concentrations in serum were higher than in the corresponding FF. However, wide variations in SARS-CoV-2 Ab titers were observed between different FF, correlating to trace element levels, even when retrieved from the same donor.

Discussion: Overall, FF contents are highly variable, but no negative association was observed between Ab in serum or FF and fertilization success and oocyte development, supporting the safety of SARS-CoV-2 vaccination during assisted reproduction.

Keywords: COVID-19; fertility; reproduction; selenium; trace elements; woman’s health.

Figure 1

Correlation of COVID-19 parameters of serum and follicular fluid samples. SARS-CoV-2 Ab and neutralizing activity yielded linear correlations in (A) serum, and (B) the follicular fluid samples. A direct comparison showed (C) no significant, or (D) a significant correlation of matched serum and folliclular fluid samples in the binding assay and neutralization test, respectively. (E) The analysis of different follicular fluids from the same donor indicated significant linear positive correlations of the binding indices and the neutralization results in samples from the vaccinated but not from the non-vaccinated women. Correlation analysis by Spearman`s rank test.

Figure 2

Comparison of SARS-CoV-2 vaccination parameters between paired serum and follicular fluids. SARS-CoV-2 Ab titers differed strongly between different follicular fluids from the same donor, with some samples reaching values as high as in serum (A), whereas others being close to unvaccinated samples, i.e., background. (B) Neutralization activities were similar in some follicular fluids to the corresponding serum sample, whereas others were below the threshold for positivity. Collectively, SARS-CoV-2 Ab titers showed high variations in different follicular fluids from the vaccinated women (Patients 1-3), and were low in non-vaccinated samples (Patients 4, 5).

Figure 3

Trace elements and vaccination parameters in follicular fluids from five individual donors. Five donors (left; three vaccinated. right; two non-vaccinated women) provided ten follicular fluids, each labeled by a different color. Relative concentrations in the samples are shown for the trace elements copper (Cu), iron (Fe), selenium (Se), and zinc (Zn), and for the vaccination parameters COVID-19 antibody concentration (COVID-19 Ab) and neutralization activity. The individual dots indicate the relative amount (fold change) to the mean per full data set from all the available samples. In general, trace elements and immunoglobulins were associated in a given follicular fluid, and a follicle with high trace element concentrations also contained on average relatively high vaccination parameters, and vice versa for relatively low values of minerals and antibodies. Colors: Each color stands for one individual follicular fluid of a participant, connected by a thin black line.

Figure 4

Association of SARS-CoV-2 antibodies on ART. No associations between successful fertilization of oocytes or the number of empty follicles and (A) concentrations of SARS-CoV-2 Ab, or (B) neutralization activities of the follicular fluids were detected. Similarly, decision to discard or to transfer the oocyte was not associated with (C) concentrations of SARS-CoV-2 Ab, or (D) the neutralization activities of the follicular fluids from which the oocytes were isolated. Pairwise comparisons were conducted by Wilcoxon rank sum test and Kruskal-Wallis test.