COVID-19 Vaccine and Ovarian Reserve

Introduction:

Although there is as yet no scientific evidence that a SARS-CoV-2 virus infection could have
negative effects on fertility, currently the possibility that the virus could affect sperm
function and egg performance cannot be excluded. Previous studies have already shown an
association between influenza and infertility. SARS-CoV-2 seems to be far more aggressive in
terms of severe illness, morbidity and mortality in comparison to common influenzas, thus it
is reasonable to hypothesize a possible substantial effect of Covid-19 on fertility.

At the cellular level, common influenza viruses promote oxidant-sensitive pathways, leading
to increased oxidative stress. This mechanism has been blamed to cause male infertility
through a reduction of progressive motility in spermatozoa and a simultaneous increase in
sperm DNA fragmentation. Based on this pathogenic pathway, it can be hypothesized that
SARS-CoV-2 could increase sperm DNA fragmentation, which might affect fertilizing potential.
Along the same lines, SARS-CoV-2 may affect oocyte performance through mechanisms that
increase oxidative stress.

As SARS-CoV-2 acts through the angiotensin-converting enzyme 2 (ACE2) receptor, this was
proposed as an additional pathway affecting ovaria follicles and oocytes. ACE2 receptors are
expressed in human ovaries, while angiotensin has been detected in measurable amounts in the
follicular fluid . Therefore, a possible negative impact of the virus through an interaction
between the oocyte and the somatic cells cannot be ruled out.

The COVID-19 pandemic exerted tremendous pressure on scientists to develop safe and effective
vaccines. A few delivery systems for next-generation vaccines against COVID-19 were
introduced. The new-generation vaccines include only a specific antigen or antigens of the
pathogen, instead of the whole pathogen, thus providing a better safety profile. While
SARS-CoV-2 has four main structural proteins, the spike protein (S) which is located at the
outer surface of the virus particles and can bind to ACE2 on the cell surface and causes
receptor-mediated endocytosis of the virus, is the main target to evoke the self-immune
system.

The mRNA vaccines represent the newest generation of vaccines in which all components can be
engineered via chemical synthesis. Due to the mRNA molecules' low apparent transfection
efficacy, lipid nanoparticles (LNPs) are often used to incorporate the mRNA molecules for
transfection purposes. An additional advantage of the mRNA vaccine is that the antigen
expression generated by the mRNA is a transient process and therefore the risk of host DNA
integration is negligible. Furthermore, elimination of live materials poses an advantage from
a quality control standpoint and allows quick product switching in manufacturing facilities.
Since the process is fully-synthetic it also eliminates the risk of disease transmissions
from the manufacturing facility. The effect of the systemic generation and introduction of
just the S protein of the SARS-CoV-2 could have a negative influence on ovarian follicles and
oocytes has not been studied yet.

Anti Mullarian Hormone (AMH) is a glycoprotein produced by the granulosa cells of the antral
follicles. Its circulating levels are associated with the fertility state of the ovary and in
contrast to other hormones are not influenced by the state of the menstrual cycle. Therefore,
AMH levels are considered the measurement of choice for estimating ovarian reserve.

As Israel is the first country to widely vaccinate its population using the mRNA vaccines and
due to all the aforementioned, the aim of this study is to evaluate the influence of the mRNA
vaccines on ovarian reserve estimated by the change in AMH before and three-month following
vaccination.

Material and Methods:

This is a prospective study including females that are planning to be vaccinated in Israel.
Women will be asked to sign an informed consent to participate in the study while visiting
the ambulatory vaccinating clinics before being vaccinated. Medical information will be
collected by the research team during this visit using computerized questionnaire. Blood
samples will be collected for AMH analysis before administration of the first mRNA vaccine
shot. A follow up visit will be scheduled at three months after the first vaccination. During
this visit, blood samples will be collected for AMH levels and for anti Covid-19 antibody
levels (Serology). Additionally, women will be asked to complete a second computerized
questionnaire which focused on possible adverse effects following vaccinations and
gynecological well-being at 3,6 and 12 months from recruitment.