Notice of Special Interest (NOSI) to Encourage Administrative Supplement Applications to Investigate COVID-19 Vaccination and Menstruation (Admin Supp Clinical Trial Optional)

NOT-HD-21-035

Key Dates

Related Announcements

PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

NOT-HD-20-021 - Notice of Special Interest: Emerging Viral Infections and their Impact on the Male and Female Reproductive Tract

Issued by

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Office of Research on Women's Health (ORWH)

Purpose

Regular menstruation is a complex function that involves the hypothalalmus, pituitary gland, ovaries, and responsiveness from the endometrial lining of the uterus, among other tissues. Regular ovulation and menstruation can therefore be an indicator of whole body health and indeed has been called by some the fifth vital sign. Due to the intricate interplay of tissues, cells, and signaling (including hormonal and other endocrine signals), the menstrual cycle can be acutely sensitive to internal or environmental variables: temporary changes in menstrual cyclicity or characteristics (duration, flow, or accompanying symptoms such as pain) can be seen in response to changes in stress, weight, diet, medications, inflammatory reactions, and systemic illness.

While anecdotal first person reports of menstrual changes in response to SARS-CoV-2 vaccines exist, these associations, and their long-term consequences, have not been investigated in a rigorous or systematic manner. Clinical trials for the Pfizer, Moderna, and Johnson & Johnson SARS-CoV-2 vaccine seem to have collected last menstrual period (LMP) data (to exclude current pregnancies), but have not collected menstrual cycle outcomes post-vaccine. To date, the U.S. Vaccine Adverse Event Reporting System (VAERS) has recorded only a small number of menstrual-related adverse events among the more than 72 million women who have been vaccinated (including menstruation irregular(n=95), menstrual disorder(n=79), menstruation delayed(n=33) ).

Viable theoretical mechanisms for vaccine-related menstrual changes do exist, including (but not limited to):

1. Menstruation itself is an inflammatory process with the recruitment of natural killer cells, macrophages, mast cells, neutrophils, dendritic cells, and T cells playing roles in the breakdown and regeneration of the functional endometrium each cycle. This inflammation (and/or the immunomodulatory molecules, such as cytokines and chemokines involved locally) could be influenced by the systemic immune response to the SARS-CoV-2 vaccine.
2. The ACE-2 receptor, the target of the spike protein of SARS-CoV-2 in a range of biologic tissues, is expressed in the uterus and is thought play a functional role in the differentiation of the endometrial fibroblasts to the decidual stromal cells in the secretory phase prior to menstruation.

However, there are also numerous potential mechanisms by which COVID-19 itself, changes in contraceptive use, or pandemic-related stress may also result in menstrual changes. Quantifying the prevalence of menstrual changes after vaccination in comparison to unvaccinated control populations is therefore necessary to demonstrate whether these changes can be linked to vaccination itself, elucidate the duration of such changes, and begin to understand the mechanism of these vaccine-related menstrual changes, if present. These studies are necessary to reduce vaccine hesitancy among those who menstruate through fuller understanding and transparency of potential vaccine-related menstrual changes.

The purpose of this NOSI is to call for targeted supplement applications to examine the impact of SARS-CoV-2 vaccines on menstruation.

Potential applicants should be advised that these supplements are likely to be highly competitive. Pending availability of funds and sufficient meritorious applications, NICHD intends to fund 3-4 supplement awards. Interested individuals with concepts that do not conform to strict responsiveness criteria listed here are urged to consider the active NICHD NOSI, Notice of Special Interest: Emerging Viral Infections and their Impact on the Male and Female Reproductive Tract utilizing R21 and R01 mechanisms.

Responsive applications for this request will:

• Be within scope of the NICHD-supported parent award (please contact Dr. Candace Tingen candace.tingen@nih.gov) if you have questions regarding scope).
• Use validated measures. Proposal of a proof-of-concept study for an exploratory platform or otherwise using unvalidated measures or tools will be considered non-responsive.
• Include participants from diverse/understudied populations. Studies of adolescent populations are acceptable.
• Utilize an existing cohort, data set, or biorepository, with or without recruitment of additional participants. Proposal of de novo assembly of entirely new study populations or cohorts will be considered non-responsive.
• If a postpartum cohort is enrolled, will also include non-postpartum persons of reproductive age. Studies of only recently postpartum individuals (within 6 months of giving birth) will be considered non-responsive.
• Utilize a US-based study population. Studies of only international cohorts will be considered non-responsive, as vaccination rate and type of vaccine may not be applicable to the US population.
• Utilize large cohorts or otherwise be well-powered with few confounders; if confounders are present, they must be rigorously controlled for. For this reason, primary focus (i.e., constituting the entirety or majority of participants) on the following populations may be considered non-responsive or lower priority: those who are infertile/subfertile, lactating, pre-menarchal or peri-/post-menopausal, substance-dependent, HIV-infected, immunosuppressed, or on hormonal contraception/other hormone therapy (including transgender men). Members of these groups may be INCLUDED, but only if "control" participants not from these subgroups are also included in numbers that allow for the analysis of the confounder.

Projects of high priority for this request include, but are not limited to:

• Studies that include baseline (pre-vaccination) menstrual health data collected prospectively, not retrospectively.
• Studies that address mechanism of action for vaccine-related menstrual changes, if found.
• Studies that account for the effect of non-vaccine variables of the current environment, such as stress, on menstrual health.

Office of Research on Women's Health (ORWH) areas of research interest

The 2019-2023 Trans-NIH Strategic Plan for Women's Health Research includes goals and objectives that aim to increase and improve women's health research supported by NIH. Goal one of the strategic plan is to advance rigorous research relevant to women's health. Incorporating a sex-and-gender lens into NIH’s response to COVID-19 offers several unique opportunities to promote rigorous research and advance health equity, including strengthening vaccine efficacy and dosing for all sexes; enhancing investigations of new therapeutics; exploring sex differences in medication risk profiles; elucidating gender-related factors affecting treatment adherence, access to health care, and health-seeking behaviors; and understanding the long-term mental and physical health consequences of isolation, stress, economic hardship, and other pandemic-associated factors. ORWH is interested in supporting research on the impact of COVID-19 disease and pandemic-related stress on women's health and on female-specific conditions and diseases, including reproductive stages and maternal and gynecologic health. Also, as an essential part of addressing this mission, ORWH is interested in supporting research on the impact of SARS-CoV-2 vaccines on menstruation and menstrual irregularities reported after vaccination. To be transparent on the effects of the SARS-CoV-2 vaccines and reduce vaccine hesitancy among people who menstruate, we need to understand the potential vaccine-related menstrual changes.

Specific areas of interest include but are not limited to:

• Identify the immediate, mid-, and long-term effects of exposures on health and disease outcomes.
• Expand research on female-specific conditions and diseases, including reproductive stages and maternal and gynecologic health, to investigate female reproductive health and illness, including menstruation and menstrual irregularities.

Application and Submission Information

Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent.

• PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

All instructions in the SF424 (R&R) Application Guide and PA-20-272 must be followed, with the following additions:

• Application Due Date(s) June 17, 2021, by 5:00 PM local time of applicant organization.
• For funding consideration, applicants must include NOT-HD-21-035 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
• Requests may be for one year of support only.
• The Research Strategy section of the application is limited to 6 pages.
• Indicate the title of this request, COVID19 Vaccination and Menstruation , in the abstract.
• Applicants are strongly encouraged to notify Dr. Candace Tingen (candace.tingen@nih.gov) that a request has been submitted in response to this FOA in order to facilitate efficient processing of the request.
• Only electronic submissions will be accepted for this funding opportunity. Use one of the methods described in PA-20-272. Paper submissions and applications submitted as attachments will be returned.
• The process for Streamlined Submissions using the eRA Commons cannot be used for this initiative.

Eligibility:The scope of this FOA is limited to parent awards focused on clinical research (human samples or subjects research, clinical trials not required). Studies of model systems will be considered non-responsive. Administrative supplements can be sought through all non-training grant mechanisms, including small business innovation research and technology transfer applications. Supplements to non-NICHD parent awards will be considered for compelling proposals. Contract mechanisms will not be eligible for this administrative supplement opportunity. Awards in no cost extension (NCE) or bridge funding will be considered eligible, but the length of the proposed project cannot extend past the end date of the current funding. Applicants should therefore consider whether the project can be completed in time remaining, as this timeline will be a factor in review.

Award Duration: Award duration is limited to one year and may not extend past the project end date of the parent award.

Award Budget: Total costs for a supplement application cannot exceed $300,000 total costs.

Review Process: NICHD will conduct administrative reviews of all supplement applications. No written critique will be provided and resubmissions are not allowed.

Review criteria will include:

1. The speed at which the proposed study can be implemented and produce findings.
2. How well the application addresses high priority topics outlined above.
3. The degree to which the proposal addresses potential menstrual changes related to COVID-19 vaccination in the US population.
4. Demonstrated success of the team, progress of the parent award, and/or strength of existing resources.

Inquiries

Please direct all inquiries to:

Candace Tingen, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 240-515-4176
Email: candace.tingen@nih.gov

Elena Gorodetsky, MD. PhD
Office of Research on Women’s Health (ORWH)
Tel: 301-594-9004
Email: egorod@mail.nih.gov