More than 138.3 million people are known to have contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with over 2.9 million deaths. Jerusalem, in Israel, is a city that has been among the hardest hit, with a very high incidence of infection.
A new study by researchers in Jerusalem, which has been released as a preprint on the medRxiv* server, indicates that while specific antibodies to the virus are present in both serum and ovarian follicles following infection or vaccination, there is no apparent adverse effect on follicular function as a result.
Vaccination in Israel
Israel is among the frontrunners in the COVID-19 vaccine rollout, which began there in December 2020. The vaccine used was the Pfizer-BioNtech vaccine (BNT162b2) which is based on a messenger ribonucleic acid (mRNA) platform that encodes the viral spike antigen within the host cell.
By the close of March 2021, over 5.2 million and 4.7 million people had received one and two doses of the vaccine, respectively, representing over half of the country’s population.
People of reproductive age were targeted in the second phase, beginning January 2021. By the end of March 2021, one dose had been completed in 72%, 77% and 82% of those aged 20-29 years, 30-39 years, and 40-49 years, respectively.
Both doses had reached the target of 61%, 68% and 75% of people in these groups. These are among the highest vaccination proportions in the world so far.
Vaccine hesitancy from fertility concerns
The hesitancy to open up vaccination among those of reproductive age stems from a lack of evidence about the vaccine's effect on fertility in those vaccinated. The current study aimed to answer this question in those affected by natural infection, as well as to vaccine recipients.
The researchers focused on follicular function in human ovaries, in terms of follicular steroid production and its response to natural triggers, and a biomarker of human oocyte quality. The measurements were carried out in the follicular fluid from patients in whom ovum pickup was being performed as a part of assisted reproduction techniques.
All of the 32 patients were between 18 and 44 years of age and had a normal ovarian response.
The SARS-CoV-2 status was recorded for each patient as well, whether infected or vaccinated. Nine were vaccinated (group 1); nine had recovered from COVID-19 (group 2); and 14 were not exposed or vaccinated (group 3).
In the vaccinated group, 4 had received only one dose. The mean delay between vaccine and study was 11.7 days in these four patients, vs. 28 days in the remaining five.
The patient’s serum and follicular fluid were evaluated in each case, for spike receptor-binding domain (RBD) IgG; for estradiol and progesterone; and follicular fluid Heparan Sulphate Proteoglycan II (HSPG2). The latter is the strongest biomarker of oocyte fertilization and successful in vitro fertilization.
What were the results?
The patients were being treated for infertility (male-related or non-male-related) or for oocyte cryopreservation, with non-female infertility making up 50% of each group, on average.
The medical protocol used meant that human chorionic gonadotropin (hCG) was used in less than a tenth of cases, but a gonadotropin-releasing hormone (GnRH) was used in 44% of group 1 and 2 patients and 29% of group 3 patients to trigger ovulation.
Anti-COVID IgG antibodies
The concentration of IgG against SARS-CoV-2 in both serum and follicular fluid (FF) was high in all recipients of two vaccine doses. In those who had received only one dose, no measurable antibodies were present in serum or FF within 8 days, but at 13 and 18 days from the first dose, IgG levels were detectable.
Serum IgG detection was positively correlated with FF IgG. This was so whether the woman had been vaccinated or exposed to infection.
All groups showed similar serum estradiol concentrations on the day of trigger administration, that is, 36 hours before the ovum pickup. The value of the serum estradiol on trigger day/oocyte was within the optimal range for most patients.
On the same day, serum progesterone was lower among controls compared to the other two groups, but not on the day of ovum pickup, when all groups had comparable values.
Both estradiol and progesterone concentrations were higher in FF vs. serum, when measured on the same day, by several hundredfold. However, all groups had comparable values for each hormone in the FF.
The follicular response to the ovulation trigger hormone was found to be adequate, as assessed by the high oocyte yield at 152% (oocytes retrieved per mature follicle count on the trigger day) in all groups.
So was the ratio of mature oocytes to total aspirated oocytes, at a mean of 0.72. Finally, the number of oocytes aspirated to the serum progesterone on the same day was also within the optimal range.
The mean HSPG2 level was around 6,300 for all samples, irrespective of group.
What are the implications?
The findings indicate that female fertility is not affected either by SARS-CoV-2 infection or by the Pfizer vaccine, but the vaccine is linked to significant protection against infection with its potential for severe or critical COVID-19, on the other hand.
The current study shows the presence of anti-SARS-CoV-2 IgG in both vaccinated and recently infected women of reproductive age, beginning, in the former group, at within two weeks from the first dose. The antibody was found in both serum and follicular fluid.
While the specific IgG level in serum and FF reflected the duration from the time of vaccination, the FF levels were correlated with those in serum.
No significant biological differences were seen in regard to reproductive parameters, following either natural infection or vaccination in any group.
The study indicates that though ovarian follicles are exposed to specific SARS-CoV-2-directed IgG antibodies following infection or vaccination, there is no adverse effect on the outcome in terms of oocyte maturation and ovarian hormone production, compared to unexposed women.
Further and larger studies will be necessary to validate and extend these findings in the target population.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.