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Are the SARS-CoV-2 Vaccines Safe for Pregnant and Lactating People?

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by Gertrud U. Rey

Vaccination is the gold standard for preventing infectious diseases and reducing the impact of emerging pathogens. As more and more people are becoming immunized against SARS-CoV-2, a prominent question continues to arise: are the vaccines safe for pregnant and breast-feeding people?

(Image credit: Shutterstock)

None of the clinical trials for SARS-CoV-2 vaccines included pregnant or lactating subjects. Pregnant people in particular are a historically difficult group to study in the context of drug safety because of concerns of liability over potential adverse effects of a new product on a fetus. This lack of safety data further complicates treatment of SARS-CoV-2 infection in pregnant people, who already have an increased risk for premature birth and miscarriage if they become infected. Based on these risk factors, the currently available data, and interim recommendations by the Advisory Committee on Immunization Practices for people over the age of 16, the American College of Obstetricians and Gynecologists recommends that pregnant and lactating people should have access to SARS-CoV-2 vaccines. Fortunately, many pregnant and lactating people have opted to be vaccinated, and the data on the safety and efficacy of vaccination in these two cohorts are beginning to emerge.

A recent publication in the American Journal of Obstetrics and Gynecology describes the safety and immunogenicity of SARS-CoV-2 vaccines in pregnant and lactating women compared to non-pregnant controls and women who had been naturally infected with SARS-CoV-2 during pregnancy. The researchers collected blood and breast milk from 131 women of reproductive age, including 84 pregnant, 31 lactating, and 16 non-pregnant participants who had received two doses of either the Pfizer/BioNTech or Moderna mRNA COVID-19 vaccine; and analyzed the samples for the presence of IgG and IgA antibodies. IgG antibodies are mostly present in the blood and provide the majority of antibody-based immunity against invading pathogens. IgA antibodies are predominantly found in mucus membranes and the fluids secreted by these membranes, including saliva, tears, and breast milk. IgA antibodies are particularly suitable for protecting against pathogens like SARS-CoV-2, which invade the body through these membranes.

Samples were collected at the time of the first and second vaccination, 2 to 6 weeks after the second dose, and at delivery. The researchers also collected umbilical cord blood from 10 infants born during the study period.

The main findings were as follows. Side effects resulting from vaccination were rare and occurred with similar frequency in all participants. These findings are consistent with post-vaccination data tracked by the CDC via the V-safe application, suggesting that post-vaccination reactions in pregnant people are not significantly different from those in non-pregnant people.

Pregnant, lactating, and non-pregnant vaccine recipients produced significantly higher levels of SARS-CoV-2-specific IgG than pregnant women who had been naturally infected. Interestingly, the second vaccine dose led to increased concentrations of coronavirus-specific IgG but not IgA, in both maternal blood and breast milk. The authors speculate that this lack of IgA boosting may have to do with the intramuscular route of immunization, which usually does not induce very high levels of serum IgA. The role of IgA in the serum is mostly secondary to IgG, in that IgA mediates elimination of pathogens that have breached the mucosal surface. In contrast, natural infection induces higher levels of mucosal (IgA) antibodies because SARS-CoV-2 enters the body through the mucosal surfaces. Nevertheless, studies have shown that IgG in breast milk is critical for protecting newborns from other pathogens like HIV, RSV, and influenza. It is possible that this type of antibody is equally important for protecting infants from SARS-CoV-2.

It was previously unclear whether vaccine-induced SARS-CoV-2 antibodies are transferred across the placenta to the fetus. However, the authors also found vaccine-induced IgG in cord blood, suggesting that these antibodies do cross the placenta, as has been previously observed after vaccination of pregnant people against influenza virus, Bordetella pertussis, and other pathogens. Whether these antibodies protect the baby from SARS-CoV-2 infection after birth, remains to be determined.

This study provides the first set of clinical data suggesting that vaccination of pregnant and lactating people against SARS-CoV-2 is both safe and beneficial. Some people have expressed concern over the possible incidence of fever following the second vaccine dose in pregnant people; however, the potential risk to the fetus from a 24-hour fever must be weighed against the possibility of chronic, severe COVID-19 in the mother. Accumulating data suggest that the benefits of vaccination during pregnancy and lactation outweigh the risks of adverse effects to the fetus or infant and align with the abundance of clinical data showing the beneficial effects of vaccinating these groups of people against influenza virus. Analyses of cord blood from infants whose mothers were naturally infected with SARS-CoV-2 during pregnancy indicate that the potential for transfer of antibodies is greater early during gestation, suggesting that immunization during the earlier stages of pregnancy might be preferable. However, more studies are needed to assess the optimal timing of maternal vaccination to achieve enhanced neonatal immunity. In the meantime, these preliminary data allow pregnant and lactating people to make more informed decisions, and also aid physicians in providing evidence-based recommendations.

Zika virus infection causes neurological deficits without microcephaly

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FlavivirusChildren who are exposed to Zika virus in utero may develop structural defects of the cranium such as microcephaly. Now we understand that even children born to Zika virus infected mothers may develop neurodevelopmental and neurosensory deficiencies in the second year of life – in the absence of microcephaly.

During the 2015-16 Zika virus epidemic in Rio de Janeiro, Brazil, a cohort was established of 244 pregnant women who tested positive for the virus. There were 223 live births in this cohort, and 8 of 216 babies were identified with microcephaly. Between 7-32 months of age, these children had clinical (hearing and eye exam) and neurological evaluations, the latter using the Bayley scales of infant development (which assess cognitive, language, and motor skills).

[Read more…] about Zika virus infection causes neurological deficits without microcephaly

Zika virus and microcephaly

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FlavivirusThree reports have been published that together make a compelling case that Zika virus is causing microcephaly in Brazil.

An epidemic of Zika virus infection began in Brazil in April 2015, and by the end of the year the virus had spread through 19 states, many in the northeastern part of the country. Six months after the start of the outbreak, there was a surge in the number of infants born with microcephaly. It was not known if most of the mothers had been infected with Zika virus, as results of serological tests, virus isolation, or PCR were not available.

An initial report of 35 Brazilian infants with microcephaly born to women who either resided in or traveled to areas where Zika virus is circulating revealed that 74% of mothers had a rash (one sign of Zika virus infection) in the first or second trimester. At the time of this study no laboratory confirmation of Zika infection was available, but the infants did not have other infections associated with birth defects, including syphilis, toxoplasmosis, rubella, cytomegalovirus or herpes simplex virus.

Yesterday the CDC reported on the analysis of tissues from two infants with microcephaly who died within 20 hours of birth, and two miscarriages, all from the state of Rio Grande do Norte in Brazil. The mothers all had rashes typical of Zika virus infection in the first trimester of pregnancy, but were not tested for infection.

All four specimens were positive for Zika virus RNA by polymerase chain reaction (PCR) done with primers from two different regions of the viral RNA. Staining of tissues with anti-viral antibodies revealed the presence of viral antigens in two of the four samples, in the brain of one newborn and in the placenta from one of the miscarriages.

A second report from the University of Sao Paulo documents ocular abnormalities in Brazilian infants (from the state of Bahia) with microcephaly and presumed Zika virus infection. The mothers of 23 of 29 infants (79.3%) with microcephaly reported signs of Zika virus infection (rash, fever, joint pain, headache, itch, malaise). Of these, 18 (78.3%) had symptoms during the first trimester of pregnancy, 4 (17.4%) during the second trimester, and 1 (4.3%) during the third trimester.

No laboratory results were available to confirm Zika virus infections, but toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and HIV were ruled out.

Abnormalities of the eye were found in 10 of 29 (34.5%) of infants with microcephaly. These included focal pigment mottling, chorioretinal atrophy, optic nerve abnormalities, displacement of the lens, or a hole in the iris.

These observations suggest that Zika virus infection may also cause lesions of the eye, although confirmation of infection needs to be done to prove causation. This uncertainty is reflected in the title of the article: “Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil” (italics mine).

The final paper is, in my opinion, the blockbuster. In this single case report, a 25 year old European woman working in Natal, Brazil, became pregnant in February 2015. In the 13th week of gestation she had fever, muscle and eye pain, and rash. Ultrasound in Slovenia at 14 and 20 weeks revealed a normal fetus.

At 28 weeks of gestation fetal abnormalities were detected, including microcephaly, and the pregnancy was aborted. Autopsy revealed severe brain defects, and 42 to 54 nm virus particles were detected in the brain by electron microscopy.

Infection with a variety of microbes was ruled out, but Zika virus RNA was subsequently detected in brain tissue by PCR.

Here is the clincher – the entire Zika virus genome was identified in brain tissue by next-generation sequencing! Analysis of the sequence revealed 99.7% nucleotide identity with a Zika virus strain isolated from a patient from French Polynesia in 2013, and a strain from Sao Paulo from 2015. These findings agree with the hypothesis that the current Brazilian outbreak was triggered by a virus from Asia.

Up to now there have been few data that strongly link Zika virus infection to congenital birth defects. Of these three new studies, the recovery of a full length Zika virus genome from an infant with microcephaly is the most convincing. Given the rapidity by which new data are emerging, it seems likely that additional evidence demonstrating that Zika virus can cause microcephaly will soon be forthcoming.

I’m amazed that a flavivirus can cause birth defects – when no flavivirus has done so before*. This is a virus spread by mosquitoes, and to which most of the world is not immune. The Zika virus outbreak will surely test our ability to respond rapidly with substantial mosquito control, diagnostics, antivirals, and a vaccine.

Update 2/11/16: A second paper has been published documenting ocular abnormalities in ten infants born to mothers in Brazil who had symptoms consistent with Zika virus infection.

Update 2/12/16: *Japanese encephalitis virus and West Nile virus have been shown to cross the placenta and infect the fetus. Such events must be rare because a larger association with birth defects has not been reported.

TWiV 71: Please Mr. Postman

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Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Rich Condit

Vincent, Dickson, Alan, and Rich answer listener questions about maternal infection and fetal injury, viral gene therapy, eyeglasses and influenza, filtering prions from blood, eradication of rinderpest, Tamiflu resistance of H1N1 influenza, bacteriophages and the human microbiome, H1N1 vaccine recalls, human tumor viruses, RNA interference, and junk DNA.

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Severe cases of pandemic influenza

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flu-pediatric-deathsThe World Health Organization recently convened a meeting of 100 clinicians, scientists, and public health professionals to discuss the clinical features of pandemic influenza. They concluded that the vast majority of infections with the 2009 H1N1 influenza virus were uncomplicated and are followed by full recovery within 7 days. However, some patients, including children, develop severe, progressive fatal pneumonia. Should we be worried about this pattern of infection?

According to WHO:

Concern is now focused on the clinical course and management of small subsets of patients who rapidly develop very severe progressive pneumonia. Treatment of these patients is difficult and demanding, strongly suggesting that emergency rooms and intensive care units will experience the heaviest burden of patient care during the pandemic. Primary viral pneumonia is the most common finding in severe cases and a frequent cause of death. Secondary bacterial infections have been found in approximately 30% of fatal cases. Respiratory failure and refractory shock have been the most common causes of death.

The risk of severe illness is highest among pregnant women, children less than 2 years of age, and individuals with chronic lung disease. In the US, 86 children under 18 years of age have died from H1N1 influenza infection. This number is unusually high at this early point in the influenza season, and will likely rise as the number of infections increase. Anne Schuchat of CDC has said that “this is a very brisk number, usually in a whole season that lasts from…September all the way to May, you would only have about 40 or 50 deaths so in just one month’s time we’ve had that many.”

Why do some patients develop progressive pneumonia, and why are there so many fatalities in children? There isn’t enough information to answer these questions, but here is my virological perspective. One factor is the unusual genetic makeup of the virus. The results of a number of studies in ferrets, mice, and primates have shown that the 2009 H1N1 influenza virus replicates better than seasonal strains in respiratory tissues, including the lung. One way to understand the basis for this difference is to produce reassortants of the 2009 H1N1 and seasonal H1N1 strains with one or more genomic RNAs exchanged. Does the swine-derived HA of the pandemic H1N1 strain play a role in virulence? Then put the RNA segment for this HA into a seasonal H1N1 virus and determine the effect in ferrets. Such experiments are not always definitive but always worth doing. I’m still not sure that the animal results are predictive of what happens in humans. After all, in all the ferrets and mice inoculated, the pandemic H1N1 strain causes more severe disease. That simply is not the case in humans; severe disease is only seen in rare cases.

Another factor is population immunity. The HA of the 2009 H1N1 virus is swine-derived; we have never had such extensive spread of a swine HA-bearing influenza virus in humans (the 1976 H1N1 swine virus never got out of Fort Dix). The H1N1 virus probably entered humans and pigs around 1918, then evolved independently in both species. The H1N1 virus has circulated in pigs from 1918 to the present. Transmission of the H1N1 virus in humans stopped in 1957 when the virus was replaced by the H2N2 strain. But the 1957 human H1N1 strain, which was reintroduced into people in 1977, is only distantly related to the 2009 swine-origin H1N1. If you were born before 1950, you have some protection against infection with the 2009 H1N1 strain. This factor may contribute to the susceptibility of the pediatric population to severe infection.

The increased risk of pregnant women for developing severe influenza is well known but poorly understood. Pregnant women are in general more susceptible to infectious disease than non-pregnant woman. Hepatitis A, B, and E are more lethal, and paralytic poliomyelitis was more common, in pregnant women than in others. One explanation is that hormonal differences affect immune responses, but the specific mechanism is obscure.

The 2009 influenza H1N1 strain clearly behaves differently than seasonal strains in certain populations. The papers explaining why have yet to be published, but when they do emerge I’ll be explaining them here.

Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, Muramoto Y, Tamura D, Sakai-Tagawa Y, Noda T, Sakabe S, Imai M, Hatta Y, Watanabe S, Li C, Yamada S, Fujii K, Murakami S, Imai H, Kakugawa S, Ito M, Takano R, Iwatsuki-Horimoto K, Shimojima M, Horimoto T, Goto H, Takahashi K, Makino A, Ishigaki H, Nakayama M, Okamatsu M, Takahashi K, Warshauer D, Shult PA, Saito R, Suzuki H, Furuta Y, Yamashita M, Mitamura K, Nakano K, Nakamura M, Brockman-Schneider R, Mitamura H, Yamazaki M, Sugaya N, Suresh M, Ozawa M, Neumann G, Gern J, Kida H, Ogasawara K, & Kawaoka Y (2009). In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature, 460 (7258), 1021-5 PMID: 19672242

Maines TR, Jayaraman A, Belser JA, Wadford DA, Pappas C, Zeng H, Gustin KM, Pearce MB, Viswanathan K, Shriver ZH, Raman R, Cox NJ, Sasisekharan R, Katz JM, & Tumpey TM (2009). Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice. Science (New York, N.Y.), 325 (5939), 484-7 PMID: 19574347

Munster VJ, de Wit E, van den Brand JM, Herfst S, Schrauwen EJ, Bestebroer TM, van de Vijver D, Boucher CA, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, & Fouchier RA (2009). Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science (New York, N.Y.), 325 (5939), 481-3 PMID: 19574348