In the largest study of its kind to date, researchers at Massachusetts General Hospital, Brigham and Women’s Hospital and the Ragon Institute of MGH, MIT and Harvard have found the new mRNA COVID-19 vaccines to be highly effective in producing antibodies against the SARS-CoV-2 virus in pregnant and lactating women.
They also demonstrated the vaccines confer protective immunity to newborns through breastmilk and the placenta.
The study, published in the American Journal of Obstetrics and Gynecology (AJOG), looked at 131 women of reproductive age (84 pregnant, 31 lactating and 16 non-pregnant), all of whom received one of the two new mRNA vaccines: Pfizer/BioNTech or Moderna.
The vaccine-induced titers – or antibody levels – were equivalent in all three groups. Reassuringly, side effects after vaccination were rare and comparable across the study participants.
“This news of excellent vaccine efficacy is very encouraging for pregnant and breastfeeding women, who were left out of the initial COVID-19 vaccine trials,” says Andrea Edlow, MD, MSc, a maternal-fetal medicine specialist at MGH, director of the Edlow Lab in the Vincent Center for Reproductive Biology and co-senior author of the new study.
“Filling in the information gaps with real data is key—especially for our pregnant patients who are at greater risk for complications from COVID-19. This study also highlights how eager pregnant and lactating individuals are to participate in research.”
According to the Centers for Disease Control and Prevention, individuals who are pregnant are more likely to become severely ill with COVID-19, require hospitalization, intensive care or ventilation – and may be at increased risk for adverse pregnancy outcomes.
The team also compared vaccination-induced antibody levels to those induced by natural infection with COVID-19 in pregnancy, and found significantly higher levels of antibodies from vaccination.
Vaccine-generated antibodies were also present in all umbilical cord blood and breastmilk samples taken from the study, showing the transfer of antibodies from mothers to newborns.
“We now have clear evidence the COVID vaccines can induce immunity that will protect infants,” says Galit Alter, Ph.D., core member of the Ragon Institute and co-senior author of the study. “We hope this study will catalyze vaccine developers to recognize the importance of studying pregnant and lactating individuals, and include them in trials.
The potential for rational vaccine design to drive improved outcomes for mothers and infants is limitless, but developers must realize that pregnancy is a distinct immunological state, where two lives can be saved simultaneously with a powerful vaccine. We look forward to studying all vaccine platforms in pregnancy as they become available.”
The study was also able to provide insight into potential differences between the immune response elicited by the Pfizer vaccine compared to the Moderna vaccine, finding the levels of mucosal (IgA) antibodies were higher after the second dose of Moderna compared to the second dose of Pfizer.
“This finding is important for all individuals, since SARS-CoV-2 is acquired through mucosal surfaces like the nose, mouth and eyes,” says Kathryn Gray, MD, Ph.D., an obstetrician at Brigham and Women’s Hospital and a first author of the paper. “But it also holds special importance for pregnant and lactating women because IgA is a key antibody present in breastmilk.”
Coronavirus disease 2019 (COVID-19) is caused by a novel single-stranded RNA virus (severe acute respiratory syndrome coronavirus disease 2 [SARS-CoV-2]) that was first identified in Wuhan, China, in December 2019. The virus spreads through close contact from person to person primarily by respiratory droplets or nasal discharge, causing severe acute respiratory syndrome and, in some cases, multiorgan failure as a complication of an inflammatory cascade.
Common symptoms include fever, headache, cough, fatigue, loss of sense of taste and smell, and respiratory symptoms. Although most individuals (>90%) infected with the virus are either asymptomatic or have mild symptoms, some people develop acute respiratory distress syndrome or other more severe forms of the disease, which can include thromboembolism, sepsis, or septic shock with multiorgan system failure.
In some cases, symptoms may persist or worsen for months afterward; these individuals can recover from their initial illness and continue to have months of fatigue, cognitive impairment, muscle weakness, autonomic dysfunction, low-grade fevers, or persistent shortness of breath.1, 2, 3
Following a person’s exposure, the incubation period, or time from exposure to symptom onset, for SARS-CoV-2 is typically 5 to 6 days. Once infected, individuals remain infectious for up to 10 days in moderate disease and 20 days in severe disease.4 Individuals who are symptomatic and asymptomatic can spread the disease, and an individual who is symptomatic may be actively shedding the virus 1 to 3 days before symptom onset.5, 6, 7
As of December 1, 2020, there were approximately 13.6 million cases and 269,192 deaths associated with COVID-19 in the United States.8 Racial and ethnic disparities have been seen during the COVID-19 pandemic with a higher incidence and disease prevalence among the Hispanic and Latino communities and a higher number of hospitalizations and deaths in the United States among black, non-Hispanic individuals.
According to the Centers for Disease Control and Prevention (CDC), as of December 1, 2020, 1.27 million cases (24.4%) of COVID-19 have been in Hispanic and Latino individuals, with nearly 23,000 deaths (14.9%). Furthermore, 736,854 cases (14.2%) and 28,686 deaths (18.6%) from COVID-19 were in black, non-Hispanic individuals compared with 2.7 million cases (52.1%) and 88,067 deaths (57.1%) in white, non-Hispanic individuals.
These demographic distributions can be compared with the most recent 2019 US census data in which 18% identified as Hispanic or Latino, 13.4% identified as black, and 59.7% identified as white. Disparities among these racial and ethnic groups have been well established9 , 10 and likely result from an array of societal and structural racism factors leading to increased risk of exposure and more severe disease. Long-standing social inequities and discrimination may also contribute to the increased risk of severe disease and death from COVID-19.11
Initial reports based on limited data from China did not suggest an increase in maternal or infant mortality. In addition, 2 more recent publications evaluating pregnant and nonpregnant women in the United States with laboratory-confirmed SARS-CoV-2 have provided more information on disease incidence and related morbidity and mortality.
In September 2020, Delahoy et al12 found that among 598 hospitalized pregnant women with COVID-19 between March 2020 and August 2020, 326 (55%) were asymptomatic at admission. Pregnant women who were symptomatic were found to have more severe illness, including 44 (16.2%) requiring intensive care unit (ICU) admissions, 23 (8.5%) requiring mechanical ventilation, and 2 (1%) deaths. An additional study released in November 2020 looking at characteristics of women of reproductive age who were symptomatic with laboratory-confirmed SARS-CoV-2 infection by pregnancy status found that among approximately 400,000 women aged 15 to 44 years with symptoms of COVID-19, ICU admission (10.5 vs 3.9 per 1000 cases; adjusted relative risk [aRR], 3.0; 95% confidence interval [CI], 2.6–3.4), invasive ventilation (2.9 vs 1.1 per 1000 cases; aRR, 2.9; 95% CI, 2.2–3.8), extracorporeal membrane oxygenation (0.7 vs 0.3 per 1000 cases; aRR, 2.4; 95% CI, 1.5–4.0), and death (1.5 vs 1.2 per 1000 cases; aRR, 1.7; 95% CI, 1.2–2.4) were more likely in pregnant women than in nonpregnant women.13 These data suggest that pregnant women should be counseled about the (1) likely increased risk of severe illness, including death; (2) proven measures to prevent SARS-CoV-2 infection; and (3) signs and symptoms for which to seek COVID-19 testing and treatment.
Prevention and Treatment
The ideal approach to address emerging infection in an epidemic and pandemic is prevention through social mechanisms and vaccination. The World Health Organization and CDC have recommended that all individuals wear face coverings in public settings to reduce the spread of the disease. In addition to face masks, implementation of social distancing guidelines has been recommended with the aim of reducing disease transmission. Proper handwashing and hygiene and the use of alcohol-based hand sanitizer in areas where soap and water are not readily available have been encouraged.
In addition to social distancing and personal hygiene guidelines, the biomedical industry has been busy trying to find effective drugs for the treatment and prevention of COVID-19. As of December 1, 2020, the New York Times Coronavirus Drug and Treatment Tracker had reported 22 different treatments for SARS-CoV-2 infection, with only one Food and Drug Administration (FDA)-approved drug available in the United States. Initially receiving Emergency Use Authorization (EUA), remdesivir was officially approved by the FDA in October 2020 for treating adults and adolescents diagnosed with mild to moderate COVID-19 requiring hospitalization. Remdesivir was shown in a double-blind, randomized, placebo-controlled trial to improve the median recovery time to 10 days for those who received remdesivir compared with 15 days among those who received placebo and reduce serious adverse events.14
Additional randomized treatment trials for COVID-19 are being performed worldwide, including a study in the United Kingdom, which showed that dexamethasone reduced mortality by one-third for critically ill patients on ventilators and by one-fifth for those receiving supplemental oxygen.15 Following this publication, the National Institutes of Health (NIH) recommended the use of dexamethasone for patients requiring mechanical ventilation or supplemental oxygenation while hospitalized with COVID-19, including pregnant patients.16
To date, no randomized clinical treatment or vaccine trial of COVID-19 has focused on pregnant women, despite being deemed a high-risk population by the CDC.17 Gilead Sciences, the maker of remdesivir, provided the drug for pregnant women who were hospitalized with severe COVID-19 under a compassionate use protocol.18
Data from 86 pregnant women demonstrated recovery and serious adverse event rates comparable with those in the randomized trial, thus supporting the use of remdesivir in pregnant women under the subsequent FDA approval. Both remdesivir and dexamethasone are recommended for use in pregnant women by the NIH COVID treatment panel guidelines given the existing safety data and probable maternal benefit.16
There are a number of other medications that have received EUA in recent weeks, including bamlanivimab, baricitinib combined with remdesivir, and the combinations of casirivimab and imdevimab. None of these are yet recommended for routine treatment of COVID-19 by the NIH.16
The US Department of Health and Human Services announced the framework for Operation Warp Speed on May 15, 2020, with the goal of delivering 300 million doses of a safe, effective vaccine to prevent COVID-19 by January 2021. As of December 1, 2020, the New York Times Coronavirus Vaccine Tracker had reported 57 different vaccines to prevent SARS-CoV-2 infection in human clinical trials with an additional 87 preclinical vaccines being studied in animals. Moderna was the first to launch the first-in-human phase 1 trial followed by a rapidly increasing number of clinical trials from numerous industry, federal, and foundation sponsors ranging phase 1 to 3 afterward.19
Despite recommendations from public health advocates for pregnant women, including the CDC, American College of Obstetricians and Gynecologists (ACOG), and American Academy of Pediatrics, pregnant women have not been included in any phase 2 or phase 3 COVID-19 vaccine clinical trials to date.20 , 21 Novel vaccines have been studied in pregnant women both during a pandemic situation, such as H1N1 influenza,22 and outside a pandemic, such as recent trials of respiratory syncytial virus and group B streptococcus vaccines.23 , 24 Although there are reported plans to enroll pregnant women following the completion of phase 3 trials, no manufacturer has publicly released their timeline for the initiation of such studies.
Looking Ahead and Next Steps
There are currently 3 types of vaccines (mRNA vaccine, viral vector vaccine, protein subunit vaccine) being developed and investigated in clinical trials for COVID-19 in the United States. None of these types of vaccines can cause COVID-19 because these vaccines contain instructions for producing antigens that stimulate the body’s immune system to produce antibodies against the SARS-CoV-2 proteins rather than containing the virus (or antigen) itself. mRNA vaccines work by supplying cellular material, promoting the production of SARS-CoV-2 proteins that stimulate the production of T and B lymphocytes. Vector vaccines work by exposing the body to a weakened version of a live virus inserted with SARS-CoV-2 genetic material, known as a viral vector.
The viral vector promotes SARS-CoV-2 protein production, and the body creates copies of these proteins, stimulating the production of T and B lymphocytes. Protein subunit vaccines are injected pieces of proteins that cause SARS-CoV-2 infection. These proteins are recognized as foreign and stimulate the production of T lymphocytes. For each of these vaccine types, antibodies against SARS-CoV-2 proteins will then circulate following vaccination and be present to fight against future infection.25
By the end of December 2020, it is anticipated that the FDA will approve at least 1 mRNA-based COVID-19 vaccine under EUA based on phase 3 clinical trial efficacy data. Both Pfizer and Moderna have manufactured vaccines with greater than 90% efficacy against SARS-CoV-2 (Table ).
The primary efficacy analysis of Pfizer’s BNT162b2 vaccine in more than 43,000 participants demonstrated 95% efficacy against SARS-CoV-2 infection beginning 28 days after the first dose, with 8 cases of COVID-19 in the vaccine group vs 162 cases in the placebo group. In addition, 10 cases of severe COVID-19 occurred in the placebo group and 1 case in the BNT162b2-vaccinated group.
The vaccine was well tolerated across all populations with no serious safety concerns. Minor side effects included fatigue and headache following the second vaccine dose.29 On November 20, 2020, Pfizer and BioNTech submitted a request to the FDA for EUA of their COVID-19 vaccine candidate.
Moderna’s mRNA-1273 vaccine of 30,000+ participants reported 94.1% efficacy, with 11 cases of COVID-19 in the vaccine group vs 185 cases in the placebo group. Furthermore, 30 cases of severe COVID-19 were identified in the placebo group compared with 0 cases in the mRNA-1273–vaccinated group.
Minor side effects reported being fatigue, muscle pain, headache, and pain at injection site.30 Moderna filed their request for EUA with the FDA on November 30, 2020. Approval of these vaccines and potentially others in the future will have an incredible impact on ending the current pandemic for much of the population worldwide. However, the lack of data on any COVID-19 vaccines in pregnant women raises many questions and concerns on how best to approach vaccine access and administration during pregnancy.
Pfizer-, Moderna-, and AstraZeneca-manufactured vaccines
|COVID-19 vaccine||Type of vaccine||n/N||Results||Efficacy (%)||Safety profile||Side effects|
|Pfizer Inc and BioNTech SE (BNT162b2)||mRNA||170/43,661||Vaccine group:• 8 cases COVID-19• 1 case severe COVID-19||95a||Well tolerated and efficacy consistent across age, gender, race, and ethnicity||Fatigue (3.8%)|
|Placebo group:• 162 cases COVID-19• 10 cases severe COVID-19||No serious safety concerns to date||Headache (2.0%)|
|Requires temperature control and continued storage at (−70°C or −94°F)|
|Moderna (mRNA-1273)||mRNA||196/30,000+||Vaccine group:• 11 cases COVID-19• 0 cases severe COVID-19||94.1||Well tolerated and efficacy consistent across age, gender, race, and ethnicity||Fatigue|
|Placebo group:• 185 cases COVID-19• 30 cases severe COVID-19• 1 death from COVID-19||No serious safety concerns to date||Headache|
|Pain or erythema at injection site|
|Requires temperature control (−20°C or −4°F); can be stored in refrigerated conditions for 1 mo|
|AstraZeneca (AZD1222)||Viral vector||131/11,363||Dosing regimen efficacy:• Half dose followed by full dose >30 d: 90%• Full dose followed by full dose >30 d: 62%||70b||Well tolerated across both dosing regimens|
COVID-19, coronavirus disease 2019; FDA, Food and Drug Administration.
Adapted from Pfizer and BioNTech, Moderna, and AstraZeneca.29,30,26
Craig. Coronavirus disease 2019 vaccines in pregnancy. AJOG MFM 2021.
aBeginning 28 days after receiving the first dose
bBeginning 14 days after receiving 2 doses.
In additional to vaccine distribution and accessibility, cost remains a question. Pfizer and BioNTech have set an initial price at $19.50 per dose or $39 per patient for a full 2-dose regimen. Moderna has set an initial price at $25 per dose or $50 per patient for a full 2-dose regimen. Those prices remain similar to seasonal influenza vaccine, which can cost near $40 for uninsured patients and included under preventive services for individuals with insurance.
Most commercial insurers and self-funded employer health plans will be expected to cover costs for COVID-19 vaccines though regulations established by the Departments of Labor and Treasury. Similarly, the Centers for Medicare and Medicaid Services have finalized that any FDA-approved COVID-19 vaccine will be provided with no cost coverage for seniors and individuals enrolled in government-funded health insurance programs.27
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832570/
Provided by Massachusetts General Hospital