Influenza immunization during pregnancy: Benefits for mother and infant

ABSTRACT

The serious consequences of influenza infection during pregnancy have been recognized for almost a century. In this article, we reviewed the evidence on the immunogenicity, safety and impact of maternal influenza immunization for both mother and child. After vaccination, pregnant women have similar protective titers of anti-influenza antibodies as non-pregnant women, demonstrating that pregnancy does not alter the trivalent inactivated influenza vaccine immune response. Studies from the United States, Europe and resource-constrained regions demonstrate that maternal vaccination is associated with increased anti-influenza antibody concentrations and protection in the newborn child as well as the immunized mother. Given the acceptable safety profile of influenza vaccines and the World Health Organization's recommendation for its use in pregnant women, maternal vaccination with inactivated influenza vaccine is a cost-effective approach to decrease influenza disease in newborns. However, as seen for influenza immunization in the elderly, the protective efficacy of current inactivated vaccines in protection of newborns is 50% at best, indicating significant room for vaccine improvement, which could potentially be achieved by addition of a safe and effective adjuvant. Thus, global deployment of inactivated influenza immunization during pregnancy would have substantial and measurable health benefits for mothers and their newborns.

KEYWORDS:

• adjuvant
• influenza
• immunization maternal and neonatal protection
• Vaccine

Introduction

Influenza is a major cause of morbidity and mortality worldwide each year. The state of relative immunosuppression during pregnancy and early life may contribute to increased susceptibility to infectious diseases and not surprisingly, pregnant women and newborns have been shown to be at increased risk of influenza complications including hospitalization, intensive care unit admission and death.^1-4 A US study showed that of pregnant women hospitalized with pandemic H1N1/2009 pdm infection, 22.6% required admission to intensive care units.³ Similarly, during previous influenza pandemics in 1918/1919 and 1957/1958 mortality rates were considerably higher among pregnant women than in the general population, in addition to a high rate of pregnancy loss.^5,6 In light of such data, the World Health Organization (WHO) recommends that all pregnant women receive inactivated seasonal influenza vaccine. Nevertheless, influenza vaccine coverage remains low in pregnant women, especially in resource-constrained (low- and middle-income) countries, but also in developed countries, influenced by concerns about vaccine safety, low perceived influenza infection risk and history of immunization non-receipt.⁷ We thus sought to review available data on the efficacy and safety of seasonal and pandemic influenza immunization during pregnancy to assess the level of evidence supporting the recommendation that all pregnant women should receive influenza immunization.

Literature review methods

English language publications describing influenza disease burden, vaccine efficacy and safety in pregnancy, both to mother and child, were sought through review of references cited by expert committees including the Australian Influenza Vaccine Committee (AIVC), the National Advisory Committee on Immunization (NACI) in Canada, the USA Advisory Committee on Immunization Practice (ACIP) and WHO Global Advisory Committee on Vaccine Safety (GACVS). In addition a Pubmed search was performed using a keyword search on “influenza vaccine” and “pregnancy,” with a focus on papers published within the last 20 y. Only inactivated influenza vaccine is recommended in pregnancy and so we confined our analysis to that formulation.

Pregnancy-associated immunological changes affecting vaccine responses

Pregnancy is associated with immunological as well as biochemical, mechanical, hemodynamic changes in the mother, characterized by distinct immunological phases.^8-10 Implantation, placentation and the first and early second trimester of pregnancy are characterized by a pro-inflammatory environment.^11-13 Later, during the period of rapid fetal growth and development, hormonal changes and exposure to fetal antigens, maternal immunity moves toward a more anti-inflammatory setting.^14,15 These immunological phase changes are necessary for successful pregnancy, but also affect susceptibility to infection and potentially responses to immunization. For example, pregnant women infected with H1N1/2009 pdm influenza virus had lower serum IgG2 levels when compared to infected non-pregnant women, with this reduced IgG2 being associated with dysregulated cytokine production and worse influenza outcomes.^16,17 In addition, pregnancy-associated changes in pulmonary and cardiovascular function including decreased lung capacity and tidal volume, increased cardiac output and oxygen consumption, may also contribute to worse influenza infection outcomes, as reported during the 2009 influenza pandemic.^18,19 Hence, the combination of pregnancy-associated changes in physiology plus dysregulated immune responses leave pregnant women particularly vulnerable to serious influenza-related complications, raising the important question of whether these adverse outcomes could be prevented by influenza immunization of all pregnant women.

Maternal influenza immunization effectiveness

Two small studies in the late 1970s of monovalent A/New Jersey/8/76 (HswlNl) influenza vaccine found no significant reduction in antibody responses in pregnant versus non-pregnant women.^20,21 During the 2009 pandemic, it was confirmed that inactivated monovalent H1N1/2009pdm vaccine was immunogenic in pregnant women, although a lower rate of seroprotection was seen in those who had received prior seasonal vaccination.^22-24 This was also seen in pregnant women receiving MF59-adjuvanted pandemic vaccine (Focetria®).^25,26 Pandemrix®, an AS03-adjuvanted pandemic vaccine, was similarly shown to be immunogenic in pregnant women in the UK.²⁴ Overall, 2009 H1N1 pandemic vaccine achieved high seroprotection rates of around 90% when given to pregnant women, regardless of the stage of gestation.²⁷ While the above data confirms influenza vaccines are immunogenic if administered to pregnant women, how does this translate into influenza protection? A case-control study conducted over 2 seasons confirmed that immunization of pregnant women reduced by about one-half their risk of acute respiratory illness associated with laboratory-confirmed influenza.²⁸ A randomized placebo-controlled trial similarly demonstrated administration of influenza vaccine to HIV-infected pregnant women provided a 50% reduction in laboratory-confirmed influenza in mothers and infants.²⁹ Hence, maternal influenza immunization is clearly effective in reducing maternal morbidity due to influenza.

Adjuvanted influenza vaccines in pregnancy

Inactivated seasonal influenza vaccines are estimated to provide only partial protection including in pregnant women.³⁰ Attempts have been made to use adjuvants to improve influenza vaccine immunogenicity, increase breadth of protection and enable antigen dose sparing,^31,32 with some of these adjuvanted vaccines having also been administered to pregnant women. Adjuvanted influenza vaccines currently available in Europe, contain MF59® (Novartis) or AS03 (GlaxoSmithKline, GSK Biologicals) adjuvants. MF59 is a squalene oil-based adjuvant that is contained in a seasonal influenza vaccine licensed in Europe since 1997 for use in people older than 65 y of age.^33,34 Its mechanism of action is not known but involves activation of MyD88 inflammatory pathways.^35,36 AS03 is a combination of α-tocopherol (vitamin E) and squalene in an oil-in-water emulsion and was extensively used in European global immunization campaigns during the 2009 pandemic with an estimated 380,000 pregnant women receiving this vaccine.^37-40 While one retrospective study in pregnant women suggested a trend to increased gestational diabetes and eclampsia in those that received MF59-adjuvanted influenza vaccine,⁴¹ other studies have not reported similar effects during pregnancy.^42-45 A randomized controlled clinical trial comparing MF59-adjuvanted vaccine (Focetria®) in pregnant and non-pregnant women found that a non-significant trend to a lower antibody response in pregnant women; 72% of the women reported adverse reactions, with 64% experiencing local reactions and 26% systemic reactions with malaise as the most common symptom.²⁵

Neonatal benefits of maternal immunization

Infants, particularly those < 6 months of age, have a high rate of influenza infection and hospitalization due to the functional immaturity of their immune systems.^46-49 In particular, neonates aged 0–5 months are 5 times more likely than those aged 6–23 months to be admitted to hospital for laboratory-confirmed influenza.⁴⁹ As no influenza vaccines are currently licensed for use in infants under 6 months, their protection requires an alternative strategy. Fortunately, neonates can potentially be protected by passively acquired maternal antibodies.⁵⁰ In humans, protective IgG antibodies are transferred to the fetus transplacentally before birth.^51,52 In addition, anti-influenza IgG and IgA-antibodies are also transferred to the infant via breastmilk.⁵³ Hence, maternal vaccination has the ability to also protect newborns against influenza infection.^54-56 The degree and duration of neonatal protection is directly dependent on influenza antibody titers in the mother and placental transfer efficacy, which is maximized by allowing sufficient time between immunization and delivery. The longevity of passively acquired antibody in infants depends on the initial cord blood concentration, with maternal antibody persisting in the infant's circulation for up to 6 months.⁵⁷ The effectiveness of maternal influenza immunization for infants has been assessed in many studies.^{50-52,54-56,58} In a match case-control study between 2000 and 2009 (prior to the 2009 H1N1 pandemic) infants aged <6 months born to influenza immunized mothers were found to have 90% less hospitalizations for influenza infection vs. infants of unvaccinated mothers.⁵⁶ A multi-site study in the USA between 2002 and 2009, similarly demonstrated that infants were 50% less likely to be hospitalized for influenza if their mothers were vaccinated while pregnant.⁵⁴ Infants of mothers who received influenza vaccination just 15 d before delivery were not seroprotected, suggesting that maternal influenza immunization needs to be performed at least 15 d before delivery in order to maximize neonatal protection.⁵⁴ A recent UK study estimated the effectiveness of 2013/2014 seasonal influenza vaccination during pregnancy in preventing influenza virus infection in infants under 6 months at 71% and effectiveness in preventing influenza-related hospitalization at 64%.⁵⁹

The benefits of maternal influenza immunization are not just seen in the developed world. The 2004–2005 Mother's Gift randomized clinical trial assessed effectiveness of influenza vaccine in pregnant women in Bangladesh (n = 340) randomized in the third trimester to receive either influenza vaccine or pneumococcal polysaccharide vaccine. Maternal influenza immunization reduced influenza infection in their infants by 63% during the first 6 months of life.^60-62 Influenza antibody levels in the neonates declined to baseline by 6 months of age, with an estimated half-life of maternally-acquired antibody of 42–50 days.⁶⁰ Vaccinated mothers also had significantly higher influenza-specific IgA levels in their breast milk out to 6 months post-partum.

This indicates that maternal influenza immunization has substantial benefits for both mothers and infants. Maternal influenza immunization has been recommended in the USA for more than a decade ⁶³ with the American College of Obstetricians and Gynecologists recommending that seasonal influenza immunization be considered an essential element of prenatal care,⁶⁴ with similar recommendations by WHO.⁶⁵ Indeed, the benefits of maternal immunization to prevent adverse neonatal outcomes are likely to be even greater in developing countries where resources to treat sick babies are more limited.

Safety aspects of maternal influenza immunization

Seasonal influenza vaccines have been administered to many pregnant women with no evidence of harm to the women or their fetuses, but with clear evidence of benefit from protection of both mothers and babies against the consequences of influenza infection.^66-68 During the 2000–2003 influenza season, an estimated 2 million pregnant women were immunized and yet very few adverse events were reported to the USA Vaccine Adverse Event Reporting System (VAERS), being mostly injection-site reactions and systemic reactions such as fever, headache and myalgia.⁶⁹ These data from passive vaccine safety reporting systems indicate that any potential vaccine-associated health complications are exceedingly rare.⁷⁰ A detailed systematic review evaluating the safety of influenza vaccination during pregnancy concluded that the use of inactivated influenza vaccine did not increase risk of fetal death, spontaneous abortion, or congenital malformations.⁷¹ In 2006, the GACVS urged WHO to consider recommendations for maternal seasonal inactivated influenza vaccination given the high risk to the mother from influenza and the small potential risk to mother and fetus.⁷²

Should squalene-adjuvanted seasonal influenza vaccines be used in pregnancy? Vaccine safety is paramount in pregnant women and insufficient data is available to conclude that squalene adjuvants are completely safe in pregnancy. Notably, a squalene-adjuvanted pandemic influenza vaccine (Pandemirix®, GSK) was recently found to be associated with an increased risk of narcolepsy in young children, highlighting the uncertain safety of oil-emulsion adjuvants in less studied patient populations such as young children and pregnant women.^73,74 As extensive safety data is available on use of unadjuvanted seasonal influenza vaccines in pregnancy, it is logical to continue their use in pregnant women until such time as an alternative adjuvanted seasonal influenza vaccine is shown to be more effective but at least as safe in pregnant women.

Different criteria need to be used for pandemic influenza recommendations as vaccines against circulating high pathogenicity avian influenza strains including H5N1 and H7N9 have been shown completely ineffective in humans unless formulated with an adjuvant. Given the extremely high mortality anticipated in pregnant women from a pandemic influenza outbreak, in this scenario the benefits of adjuvanted pandemic influenza vaccine approaches in pregnant women far outweigh any potential risks.

Public perceptions of maternal influenza immunization

The demonstrated benefits of influenza immunization during pregnancy have been proven to far outweigh any risks of potential rare adverse effects of vaccination. Notably, during the recent 2009 influenza pandemic, maternal vaccination became more widely accepted and this may be attributed to the high level of publicity of higher risk of influenza-related complications including death for pregnant women. Unfortunately, with passing of the pandemic scare, seasonal influenza vaccination rates in pregnant women have dropped back to previous low levels.⁷⁵ Research has shown that the largest barriers to seasonal influenza use among pregnant women in North America are beliefs that influenza infection is not serious, as well as patient and health-care provider misconceptions about vaccine safety.^76-78 Nonetheless, US studies have reported that most pregnant women would accept influenza immunization if their healthcare provider offered it.^79,80 Studies from other regions, including Asia and Europe, have identified similar barriers to pregnant women accepting influenza immunization.^81,82 In light of the seriousness of this issue the WHO convened a committee to consider the issue of “Vaccine hesitancy,” with the committee's recommendations being published in an August 2015 Special Issue of Vaccine. While the committee didn't specifically tackle the issue of vaccine hesitancy in pregnant women, they did comment on the difficulty experienced during the 2009 pandemic influenza of convincing pregnant versus non-pregnant North American women to be immunized as an important issue that needs addressing.⁸³

Future prospects

To date, experience in pregnancy has almost exclusively been with use of split inactivated influenza vaccines. However, in recent years alternative vaccines have entered the US market, most notably a seasonal influenza vaccine made from recombinant hemagglutinin protein produced in insect cells (Flublok®, Protein Sciences Corporation).⁸⁴ Approved by the FDA for use in all adults, Flublok is classed as pregnancy category B, which means that studies in animals have shown no risk. While minimal data is currently available on Flublok use in pregnant women, such data should accrue with time now it is part of the seasonal vaccine market. Notably, many other novel types of influenza vaccines are under development, including DNA and RNA vaccines as well as universal influenza vaccines based on other influenza proteins such as nuclear protein or the M2 channel. Such vaccines, given their novelty, would need considerable data in other populations, before being routinely recommended for use in pregnant women. Similarly, novel adjuvants have potential to enhance the effectiveness of both seasonal and pandemic influenza vaccines.^85,86 Again, it will first be important to establish the safety of such adjuvants in animal models of pregnancy to confirm absence of adverse reproductive, teratogenic or developmental effects.⁸⁵ One promising new adjuvant in this regard is a next-generation polysaccharide-based adjuvant developed from microcrystalline particles of delta inulin (Advax™). Advax™ has been shown to improve the immunogenicity of seasonal and pandemic influenza vaccines in non-pregnant adult human subjects.⁸⁷ Its base material, inulin, has also been extensively safely used in pregnant women as part of routine kidney function testing.⁸⁸ In animal models, Advax adjuvant markedly enhanced protection of maternally-immunized mothers but also their pups against an otherwise lethal influenza infection.⁸⁵ Importantly, Advax adjuvant had no adverse reproductive, teratogenic or developmental effects in immunized mothers or their pups.⁸⁵ Hence, along with other promising new influenza vaccine technologies currently in development, new adjuvants such as Advax could be used in the future to enhance influenza vaccine effectiveness in pregnant women and their infants.

Conclusions

The burden of influenza among pregnant women, and the excellent safety profile and immunogenicity of seasonal vaccines, support a recommendation that all pregnant women receive influenza vaccine to decrease influenza-related illness in both the mother and her baby. The 2009 influenza pandemic may have temporarily increased global awareness about the risk of influenza during pregnancy, but unfortunately this does not seem to have translated into improved levels of seasonal vaccine utilization among pregnant women, which remains highly variable. The infectious disease challenges faced by pregnant women and their babies in developing countries are major, suggesting an even bigger benefit of maternal influenza immunization than in developed countries, as demonstrated by the effectiveness of maternal influenza immunization in the Bangladesh study.⁶² It is pleasing to note that there are several randomized control trials completed, ongoing or planned in other low-income countries including Mali, Nepal and South Africa to evaluate efficacy and safety of maternal influenza immunization that include clinical or immunogenicity endpoints in newborn infants.⁸⁹ It remains critical to conduct more research into the effects of influenza infection during pregnancy and toward better strategies to overcome its adverse effects on mother and baby. In particular, there remains a need to improve the effectiveness of current influenza vaccines, which remain only partially effective in protecting the general population as well as pregnant women and their babies. It is likely the solution to this problem will come from use of adjuvants to increase vaccine immunogenicity and better induce T cell immunity, as well as from development of novel vaccine approaches that target highly conserved influenza antigens such as nuclear protein and the M2 channel. Nevertheless, it will first be important to demonstrate that such new vaccine approaches are at least as safe and well tolerated as existing inactivated vaccines, before they can be recommended for use in pregnancy. In the meantime, there remains considerable scope to reduce the global seasonal influenza disease burden in pregnant women and their babies by tackling the problem of vaccine hesitancy in this specific subgroup, thereby improving on current suboptimal immunization rates.

Disclosure of potential conflicts of interest

The authors are employed by and/or affiliated with Vaxine Pty Ltd (Adelaide, Australia).

Funding

The authors were supported by Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800039C and Collaborative Research Contact No. U01AI061142. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.