HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 12, 3065–3071 http://dx.doi.org/10.1080/21645515.2016.1215392
REVIEW
Influenza immunization during pregnancy: Benefits for mother and infant Isaac G. Sakalaa,b, Yoshikazu Honda-Okuboa,b, Johnson Funga, and Nikolai Petrovskya,b a
Vaxine Pty Ltd, Bedford Park, Adelaide, Australia; bDepartment of Diabetes and Endocrinology, Flinders University, Adelaide, Australia
ABSTRACT
ARTICLE HISTORY
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.
Received 7 March 2016 Revised 29 June 2016 Accepted 15 July 2016 KEYWORDS
adjuvant; influenza; immunization maternal and neonatal protection; Vaccine
Introduction
Literature review methods
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.
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.
CONTACT Professor Nikolai Petrovsky, Director SA, Australia 5042. © 2016 Taylor & Francis
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
nikolai.petrovsky@flinders.edu.au
Department of Diabetes and Endocrinology, Flinders Medical Center, Adelaide,
3066
I. G. SAKALA ET AL.
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 nonpregnant 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.
age.33,34 Its mechanism of action is not known but involves activation of MyD88 inflammatory pathways.35,36 AS03 is a combination of a-tocopherol (vitamin E) and squalene in an oil-inwater 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 (FocetriaÒ ) 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
Maternal influenza immunization effectiveness
Neonatal benefits of maternal immunization
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 (FocetriaÒ ).25,26 PandemrixÒ , 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 placebocontrolled 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.
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, antiinfluenza 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
REVIEW
Influenza immunization during pregnancy: Benefits for mother and infant Isaac G. Sakalaa,b, Yoshikazu Honda-Okuboa,b, Johnson Funga, and Nikolai Petrovskya,b a
Vaxine Pty Ltd, Bedford Park, Adelaide, Australia; bDepartment of Diabetes and Endocrinology, Flinders University, Adelaide, Australia
ABSTRACT
ARTICLE HISTORY
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.
Received 7 March 2016 Revised 29 June 2016 Accepted 15 July 2016 KEYWORDS
adjuvant; influenza; immunization maternal and neonatal protection; Vaccine
Introduction
Literature review methods
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.
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.
CONTACT Professor Nikolai Petrovsky, Director SA, Australia 5042. © 2016 Taylor & Francis
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
nikolai.petrovsky@flinders.edu.au
Department of Diabetes and Endocrinology, Flinders Medical Center, Adelaide,
3066
I. G. SAKALA ET AL.
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 nonpregnant 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.
age.33,34 Its mechanism of action is not known but involves activation of MyD88 inflammatory pathways.35,36 AS03 is a combination of a-tocopherol (vitamin E) and squalene in an oil-inwater 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 (FocetriaÒ ) 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
Maternal influenza immunization effectiveness
Neonatal benefits of maternal immunization
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 (FocetriaÒ ).25,26 PandemrixÒ , 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 placebocontrolled 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.
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, antiinfluenza 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
