The safety of adjuvants in influenza vaccines during pregnancy: what do we know and why do we need them?

The high mortality rates observed among pregnant women during the 1957 through 1958 influenza pandemic prompted the US Surgeon General to issue a report in 1960 that recommended routine seasonal influenza vaccination for pregnant women. During the past half century, recommendations in the United States have evolved, with influenza vaccination recommended for all pregnant women regardless of trimester beginning in 2004. Despite these recommendations, influenza vaccination rates among pregnant women were generally low (<15%) until the 2009 H1N1 influenza A pandemic when vaccination rates increased to about 50%. Although these higher vaccination rates have been sustained, we are still a long way from the goal of ensuring that all pregnant women are vaccinated against influenza. Part of the challenge with achieving this goal has been lingering concerns about safety of vaccination during pregnancy.

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Pregnant women are typically excluded from clinical trials evaluating vaccine safety and effectiveness. Therefore, most information about vaccination during pregnancy comes from observational studies conducted following US Food and Drug administration (FDA) approval of vaccines. In the case of the seasonal influenza vaccine, we have accumulated many decades of experience vaccinating pregnant women without any major concerns about safety. A review of the literature published in 2009 did not identify any studies that documented an increased risk of adverse maternal or fetal effects with maternal influenza vaccination, and subsequent reviews of safety data during and following the 2009 H1N1 pandemic have been reassuring. The influenza vaccines licensed and used in the United States, however, do not contain adjuvants. Much less is known about the safety of adjuvants in pregnancy.

Adjuvants are substances added to vaccines to boost the immune response and potentially provide longer-lasting and broader protection against antigenically drifted viruses. During a future pandemic, adjuvants could allow for use of lower doses of antigen at a time when the urgent demand for vaccine might outstrip production capacity. In addition, stockpiled prepandemic vaccines, produced against previously circulating highly pathogenic avian influenza H5N1 viruses, will likely require addition of an adjuvant to promote adequate immune response to a newly circulating H5N1 pandemic strain that has drifted antigenically since the vaccine was prepared. However, there are some theoretical concerns about the use of adjuvants in pregnancy. During pregnancy there are alterations of the immune system that occur to accommodate fetal and placental growth without triggering rejection of paternally derived antigens. How adjuvanted vaccines that elicit a robust immune response might affect pregnancy is unknown.

Introduced in the 1920s, aluminum salts are the most common adjuvants and are used in a variety of vaccines including hepatitis A, hepatitis B, human papilloma virus, diphtheria, tetanus, pertussis, polio, and pneumococcal. Available data on the use of aluminum-based adjuvants during pregnancy are reassuring. Worldwide, many pregnant women have received tetanus toxoid vaccines containing an aluminum adjuvant with no increased risk of adverse pregnancy outcomes. Newer adjuvants have been developed more recently and include the oil-in-water emulsions such as AS03 and MF59. Although the safety of these newer adjuvanted vaccines in pregnancy has not been well studied in clinical trials, the 2009 H1N1 influenza pandemic offered a rare opportunity to evaluate adjuvanted vaccines in pregnancy because many European countries used adjuvanted 2009 H1N1 vaccines to vaccinate large numbers of pregnant women.

Several studies assessed the safety of AS03-adjuvanted 2009 H1N1 vaccine in pregnant women. A relatively small prospective observational study of 267 women from the United Kingdom who were vaccinated with an AS03-adjuvanted 2009 H1N1 vaccine found no increased risk of adverse pregnancy outcomes including congenital anomalies. A larger nationwide registry study from Denmark of >7000 pregnant women vaccinated with AS03-adjuvanted 2009 H1N1 vaccine was similarly reassuring with no increased risk of spontaneous abortion or fetal death. Several small studies have assessed the safety of MF59-adjuvanted 2009 H1N1 influenza vaccines ; collectively, these studies report use of MF59-adjuvanted vaccine among a total of <150 pregnant women. In this current issue of the American Journal of Obstetrics and Gynecology is an observational study of 2295 pregnant women who received MF59-adjuvanted 2009 H1N1 influenza vaccine and a comparison group of >2213 unvaccinated pregnant women. This study found no differences in rates of adverse pregnancy or birth outcomes between vaccinated and unvaccinated women. This study, representing the largest and most complete information on MF59 adjuvant use in pregnancy to date, provides reassuring data about its safety during pregnancy. However, as noted by the authors, the study had several limitations. These include the small number of first-trimester exposures, limited power to assess relatively rare outcomes (eg, individual birth defects), and a focus on outcomes that are present at or shortly after birth. Additional studies are needed to address these critical knowledge gaps.

The 2009 H1N1 pandemic may not be the last influenza pandemic in our lifetimes. Circulation in many countries of highly pathogenic avian influenza A (H5N1) virus among birds with occasional transmission to human beings continues to raise concerns about a future pandemic. In addition, we are reminded of the risk of emergence of novel reassortant viruses by the recent reports of 13 persons in 6 US states infected with a novel reassortant influenza A (H3N2) variant (H3N2v) virus, which contains genes from human, swine, and avian influenza viruses, and the M gene from the 2009 H1N1 virus. More research is needed on the safety of adjuvanted vaccines in pregnancy, particularly their use in the first trimester, to establish a more complete safety profile. Although determination of safety of a vaccine used during pregnancy is challenging and usually depends on data from studies initiated after FDA approval, studies performed during the 2009 H1N1 pandemic provide us with reassuring data regarding use of influenza vaccines during pregnancy, including adjuvanted vaccines. These data will be useful in weighing the potential risks and benefits of use of an adjuvanted influenza vaccine in the event of a future pandemic.

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May 15, 2017 | Posted by in GYNECOLOGY | Comments Off on The safety of adjuvants in influenza vaccines during pregnancy: what do we know and why do we need them?
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