Maternal benefits of immunization during pregnancy - Core

Vaccine 33 (2015) 6436–6440

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Maternal benefits of immunization during pregnancy Geeta K. Swamy a,∗ , Richard H. Beigi b a

Department of Obstetrics and Gynecology, Duke University, Durham, NC, United States Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, United States b

a r t i c l e

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Article history: Available online 16 September 2015 Keywords: Maternal immunization Vaccine Passive immunity

a b s t r a c t The US Centers for Disease Control & Prevention currently recommend routine immunization to prevent 17 vaccine-preventable diseases that occur in infants, children, adolescents, or adults. Pregnant women are at particularly high risk for morbidity and mortality related to several vaccine-preventable diseases. Furthermore, such illnesses are also associated with adverse pregnancy outcomes such as spontaneous abortion, congenital anomalies, preterm birth, and low birthweight. In addition to directly preventing maternal infection, vaccination during pregnancy may offer fetal and infant benefit through passive immunization. Several vaccines aimed at providing passive immunity to neonates are either currently recommended or in development. This article specifically addresses maternal benefits of maternal immunization following (1) vaccines recommended for all pregnant women; (2) vaccines recommended for pregnant women with particular risk factors; and (3) novel vaccines currently under development that primarily aim to at reduce infant morbidity and mortality. © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction Pregnancy is a particularly susceptible period for maternal and infant complications associated with vaccine preventable diseases (VPDs). Pregnant women are at high risk for influenza-related morbidity and mortality, including higher rates of hospitalization, cardiopulmonary complications, and death compared to the general public [1]. Maternal influenza infection is associated with adverse birth outcomes including preterm birth, fetal growth restriction, and fetal demise [1]. Both maternal and fetal complications are further elevated during pandemic influenza seasons. Maternal–fetal transmission of varicella and rubella are associated with congenital malformations and life-long infection in the case of hepatitis B. Beyond preventing maternal and fetal infection, maternal immunization should provide infant protection through passive immunization, i.e. via transplacental transfer of maternal IgG antibodies as well as transfer of maternal IgA antibodies via breast milk [2,3]. The potential for passive immunization to protect young infants against pertussis infection has been the primary driver for the recent recommendation for administration of tetanus, diphtheria, acellular pertussis (Tdap) vaccination during each and every

∗ Corresponding author at: Duke University, 2608 Erwin Rd, Suite 210 Durham, NC 27705, United States. Tel.: +1 919 668 1600; fax: +1 919 613 1550. E-mail address: [email protected] (G.K. Swamy).

pregnancy [4]. In addition to the six vaccines (vaccines against influenza, Tdap, pneumococcus, meningococcus, Hepatitis A and B) that are currently recommended by the US Centers for Disease Control & Prevention (CDC) for use during pregnancy (with some contingent upon risk factors), novel vaccines against group B streptococcus and respiratory syncytial virus are currently being evaluated for administration during pregnancy [5–7]. Although novel vaccine candidates are focusing primarily on the potential for infant disease prevention, this article specifically addresses maternal benefits of immunization during pregnancy following: (1) vaccines recommended for all pregnant women; (2) vaccines recommended for pregnant women with particular risk factors; and (3) vaccines primarily aimed at reducing infant morbidity and mortality (Table 1).

2. Vaccines recommended for all pregnant Women 2.1. Influenza Approximately 20% of the US population will have influenza during a single non-pandemic season compared to nearly 50% during a pandemic season [1]. Similarly, 20% of pregnant women will suffer from an influenza-like illness (ILI) during a non-pandemic season, with 10% having laboratory-confirmed influenza [8]. Presumably due to changes in immunology and cardiorespiratory physiology rather than susceptibility to acquisition, pregnant and immediately

http://dx.doi.org/10.1016/j.vaccine.2015.08.035 0264-410X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

G.K. Swamy, R.H. Beigi / Vaccine 33 (2015) 6436–6440

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Table 1 Licensed and novel vaccines for pregnant women. Vaccines recommended for all pregnant women

Vaccines recommended for pregnant women with risk factors

Novel vaccines aimed at reducing infant infection through maternal immunization

Inactivated influenza vaccine (IIV)

Pneumococcal polysaccharide 23-serotype vaccine (PPSV23)

Tetanus, diphtheria, acellular pertussis (Tdap)

Meninogococcal tetravalent polysaccharide vaccine (MPSV4) Inactivated hepatitis A vaccine Recombinant hepatitis B vaccine

Trivalent group B streptococcus polysaccharide vaccine Inactivated respiratory syncytial virus vaccine

postpartum women are at high risk for influenza-related morbidity and mortality including hospitalization, cardiopulmonary complications, and death [9]. Beyond maternal complications, influenza infection in pregnancy is associated with adverse birth outcomes including spontaneous abortion, preterm birth, low birthweight, and fetal demise [1]. Both maternal and fetal complications increase even further during pandemic seasons [10,11]. Based on the potential for maternal morbidity and mortality associated with influenza during pregnancy, the CDC and the American College of Obstetrics & Gynecology (ACOG) recommend inactivated influenza vaccine (IIV) for all women who will be pregnant during influenza season [12]. Initial recommendations for IIV administration during pregnancy made in 1997 were extrapolated from the documented efficacy and safety of IIV in nonpregnant adults. Until the 2009 pandemic, there were only a few small-scale studies on the safety and immunogenicity of maternal influenza vaccination. In a randomized trial of 340 pregnant women in Bangladesh, Zaman et al. demonstrated a 36% reduction in laboratory-confirmed influenza among women who received IIV during the third trimester compared to women who received pneumococcal vaccine [2]. While this study was potentially limited by the lack of a placebo control group, Madhi et al. recently completed a randomized trial of IIV vs. placebo in ∼2000 pregnant women in South Africa [13]. With influenza attack rates of 3.6% vs. 1.8% among HIV uninfected placebo and IIV groups respectively, IIV vaccine efficacy in this pregnant population was 50.4% (95% CI 14.5–71.2). For women with HIV infection, vaccine efficacy was 57.7% (95% CI 0.2–82.1) with attack rates of 17% vs. 7% for placebo and IIV groups, respectively. Black et al. were unable to demonstrate vaccine effectiveness against hospital admissions and physician outpatient visits due to respiratory illness among pregnant women cared for in a health system level analysis over five consecutive non-pandemic seasons [14]. The lack of demonstrated effectiveness may be due to the use of respiratory illness rather than laboratory confirmed influenza and that hospitalizations among the entire population of pregnant women were uncommon, regardless of vaccination status. However, a population-based study of 117,347 Norwegian women who were pregnant during the 2009–2010 pandemic revealed a 70% reduction in clinical diagnosis of influenza, suggesting that vaccine efficacy during a novel pandemic season may offer even greater maternal benefit than seasonal vaccination [15]. Successful public health promotion by the CDC and ACOG led to influenza vaccine coverage exceeding 50% for the first time in 2012–2013 [16]. Studies assessing vaccine acceptance have clearly identified a lack of knowledge of recommendations, lack of obstetric provider recommendation, and lack or misunderstanding of safety data during pregnancy as the key factors influencing influenza vaccine uptake during pregnancy [17,18]. Thus, continued research on influenza vaccination during pregnancy and education of obstetric providers and pregnant women is warranted. With approximately 4 million births in the US annually, maternal influenza immunization has great potential to improve maternal health during pregnancy and the immediate postpartum period when the risks of influenza are greatest.

2.2. Tetanus, diphtheria, and pertussis Childhood vaccination combined with decennial booster and exposure-related dosing against tetanus and diphtheria has led to the near eradication of both diseases in the US. Pertussis or “whooping cough”, however, has been on the rise for the last two to three decades following a long period of active disease control and prevention. Although the incidence of pertussis has increased across the entire population, disease-related morbidity and mortality primarily affects infants [19]. Infants are most commonly exposed to pertussis through close contact, with 47–60% of cases due to exposure from infected parents [20]. Furthermore, adults with pertussis are often unaware of their diagnosis, given that many adults are either asymptomatic or have symptoms of a common cold. Vaccination efforts to reduce the incidence of pertussis among young infants have previously focused on cocooning, or strategies to immunize close contacts of young infants against pertussis. The initial strategy including immediate postpartum maternal vaccination combined with antenatal vaccination among previously non-vaccinated pregnant women failed to affect the ongoing pertussis outbreaks. In October 2012, the CDC changed its recommendation on vaccination during pregnancy, now advising obstetric providers to administer Tdap during each pregnancy, regardless of prior Tdap receipt [4]. This strategy is based on the concept of passive immunization in which maternally-derived vaccine-induced antibodies cross the placenta into the fetal circulation. Passive immunization can protect young infants during the first few months of life when they are most vulnerable to pertussis and prior to establishing immunity from their own primary vaccination series [20,21]. While it is imperative that we continue efforts to reduce the incidence of infant pertussis, many questions remain regarding the potential benefits and/or risks of Tdap administration during pregnancy, including the potential effect of repeated close-interval dosing among women having more than one pregnancy in a relatively short period of time, e.g. 1–3 years, and whether repeated doses of Tdap actually continues to boost pertussis antibody levels in pregnant women. Although relatively small with 48 pregnant and 32 non-pregnant, Tdap naïve women, Munoz et al. demonstrated that Tdap administration during pregnancy is immunogenic and safe [22]. However, the overall lack of data on the potential maternal benefit of Tdap vaccination, i.e., to prevent pertussis in pregnant women themselves, as well as the lack of both immunogenicity and safety data following repeated Tdap administration, represents a significant knowledge gap. Ongoing larger-scale studies of Tdap during pregnancy will provide much needed data in the near future [23,24]. 3. Vaccines recommended for all pregnant women with risk factors 3.1. Pneumococcal disease Pneumococcal disease, caused by the Gram-positive Streptococcus pneumoniae bacterium, is associated with substantial

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morbidity and mortality resulting from pneumonia, bacteremia, and meningitis [25]. Pneumococcal pneumonia, the most common manifestation, affects ∼900,000 Americans and results in 400,000 hospitalizations and 5–7% mortality each year. Less common presentations include bacteremia and meningitis, which affect about 12,000 and 3000 individuals each year, respectively, with 10–15% mortality. Although the incidence of pneumonia during pregnancy is fairly low, the disease course is similar to that of influenza, likely attributable to the same pregnancy-associated physiologic respiratory changes and alterations in cell-mediated immunity, resulting in higher rates of hospitalization, acute respiratory distress syndrome (ARDS), cardiorespiratory failure, and death [26]. Obstetric complications include fetal distress, preterm birth, and low birthweight [26]. Current CDC guidelines recommend the 23-serotype polysaccharide vaccine (PPSV23) for children and adults with chronic medical conditions and other risk factors including chronic heart or lung disease (asthma, diabetes, cigarette smoking), alcoholism, chronic liver disease, cerebrospinal fluid leaks, cochlear implants, congenital or acquired immunodeficiencies, diseases requiring immunosuppressant therapy, sickle cell disease and other hemoglobinopathies, and functional or anatomic asplenia [27]. In addition, the 13-serotype pneumococcal conjugate vaccine (PCV13) is recommended for all children and additional high risk adult subpopulations [28]. While currently available data do not support the need for widespread use of PCV13 or PPSV23 during pregnancy [29], a systematic review of observational studies and a randomized trial of PPSV23 given during pregnancy demonstrated no maternal or fetal safety concerns [22,30]. Furthermore, maternal PPSV23 vaccination provides protective antibody levels for at least one year following delivery and higher neonatal antibody levels. A recent Cochrane review found insufficient evidence to suggest that maternal vaccination could reduce infant pneumococcal infection via passive immunization [31]. Nevertheless, in accordance with CDC guidelines for adult immunization, PPSV23 should be given to pregnant women for their own benefit with additional risk factors as described above.

3.2. Meningococcal disease Neisseria meningitidis causes rare, but often deadly, meningitis and sepsis in about 1000 people in the US each year [32]. Although susceptible to antibiotics, meningococcal disease carries a mortality rate of 10–15% and a 20% rate of severe morbidity among survivors including limb amputations, strokes, and neurocognitive abnormalities. In 2005, the tetravalent meningococcal conjugate vaccine (MCV4) was included in the US adolescent vaccination schedule, replacing the tetravalent polysaccharide vaccine (MPSV4) based on a longer duration of vaccine-induced immunity with MCV4. Similar to PPSV23 and PCV13, there are several adult subgroups who are at high risk for meningococcal infection: those in close living conditions such as dormitories or military barracks, those with complement deficiencies, functional or anatomic asplenia, those residing in hyperendemic areas, and laboratory staff working with N. meningitidis. Previously unvaccinated pregnant women with risk factors for meningococcal disease should be vaccinated. Although MCV4 and MPSV4 are both inactivated products which should not carry any maternal or fetal risk, available data on meningococcal vaccination in pregnancy involves MPSV4 rather than MCV4. A systematic review of maternal MPSV4 demonstrated no concern for maternal or fetal complications [30]. O’Dempsey et al. demonstrated an adequate maternal antibody response following MPSV4 vaccination in the third trimester [33]. Given the lack of available safety data on MCV4, MPSV4 is recommended

for use during pregnancy based on risk factors described above [29]. 3.3. Hepatitis A Although generally self-limiting, hepatitis A virus (HAV) causes fever, vomiting, and jaundice due to acute liver infection. As HAV is transmitted via fecal-oral contamination from close contact with infected individuals or contaminated food or drinks, the general public is at risk for HAV infection [34]. Widespread vaccination against HAV in the US began in 1999 and has led to a significant drop in documented cases of HAV in the US [35]. Although HAV vaccination is currently included in the CDC recommended childhood immunization schedule, vaccination against HAV is also recommended for people with high risk for HAV exposure: those traveling to endemic areas, men who have sex with men, those in close contact with individuals with HAV infection or receipt of clotting-factor concentrates, and laboratory or healthcare staff working with biological specimens. Consistent with CDC guidelines, pregnant women with identifiable risk factors should receive HAV vaccine [34]. Although the data on HAV vaccine safety during pregnancy is lacking, the current inactivated HAV vaccine does not contain live virus components and is exceedingly unlikely to carry any risk of maternal or fetal harm. 3.4. Hepatitis B Associated with acute liver inflammation, vomiting, and jaundice, hepatitis B virus (HBV) can either be self-limiting or lead to a chronic carrier state with long-term morbidity (cirrhosis, liver cancer, liver failure) and mortality. Individuals with close contact with an HBV-infected individual’s blood and bodily fluids are at risk for disease. The three-dose recombinant DNA HBV vaccine series provides indefinite immunity in most individuals (>90%) and is currently initiated at birth as part of the CDC recommended childhood immunization schedule [36]. Vaccination against HBV has been proven to be effective given the greater than 60% reduction in reported cases of HBV over the last 15–20 years [35]. Much of the attention on HBV during pregnancy focuses on the risk of perinatal transmission following primary or chronic maternal infection, particularly given the high risk of chronic disease development following perinatal acquisition. As part of that focus, pregnant women are routinely screened for HBV via surface antigen (HBsAg) testing followed by neonatal treatment with HB immunoglobulin (HBIg) prophylaxis and HBV vaccination during the first hours of life for infants born to HBV infected mothers [37]. However, unvaccinated pregnant women with risk factors for HBV acquisition should be counseled on the extremely high effectiveness of HBV vaccination to prevent maternal and subsequent fetal infection. Individuals at high risk of HBV acquisition include those with one or more sexual partner in the past six months, household or sexual contact with an HBV-infected individual, or intravenous drug use [36]. Although extensive safety data are limited, HBV vaccination during pregnancy has not been associated with any maternal or fetal complications [30]. Therefore, the three-dose HBV vaccine series should be initiated for previously unvaccinated or incompletely vaccinated pregnant women with risk factors for HBV infection.

4. Novel vaccines aimed at reducing infant infection through maternal immunization Similar to the recommendation for Tdap to be administered during pregnancy, additional vaccines focused on prevention of group


B streptococcus (GBS) and respiratory syncytial virus (RSV) during early infancy are in development. 4.1. Group B Streptococcus GBS is leading cause of invasive infection within the first three months of life, resulting most commonly in sepsis and meningitis [38]. Intrapartum antibiotic prophylaxis has significantly reduced the incidence of early-onset neonatal GBS (within the first seven days of life) in the US. However, there has been no change in the rates of late-onset GBS disease (from one week to three months of age), which occurs in 0.29–0.47 per 1000 live births and can be equally devastating. Furthermore, strategies of screening plus intrapartum antibiotic prophylaxis are often impractical in low-resources settings. Based on available evidence of neonatal protection against GBS disease in the setting of passive immunity [39], a vaccine against GBS could have a significant impact on preventing both early- and late-onset disease. Albeit the primary objective of a GBS vaccine will be to reduce infant infection, it is highly plausible that a GBS vaccine would have significant benefits for maternal health and ultimately overall pregnancy outcomes. In addition to asymptomatic cervicovaginal colonization, GBS causes numerous maternal infections [40]. Although most GBS urinary tract infections are asymptomatic, GBS causes about 10% of acute pyelonephritis in pregnancy, which is highly concerning given the association of pyelonephritis with adverse pregnancy outcomes (preterm birth, low birthweight, fetal demise) [41]. Intra-amniotic infection (IAI) is caused by the ascending spread of vaginal flora, with GBS detected in the amniotic fluid of 15% of cases. Maternal consequences of IAI include serious maternal pelvic infections, sepsis, and postpartum hemorrhage. Maternal bacteremia occurs in 2–6% of IAI cases overall and in up to 35% of cases with confirmed GBS-related puerperal infection – IAI and postpartum endometritis. While septic shock is rare, GBS sepsis follows bacteremia in 5–25% of cases [42]. A trivalent conjugated GBS vaccine is being evaluated in phase II and III studies in pregnant women, with a focus on third trimester administration to theoretically maximize passive immunity at the height of antibody transfer rates [6,43]. Although the morbidity of maternal GBS infection is certainly less than that in the young infant, maternal disease occurs more frequently and endangers both mother and infant. Evaluation of the efficacy of the vaccine to prevent maternal GBS infection as well as optimal timing of administration to benefit both mother and infant will be crucial. 4.2. Respiratory syncytial virus In the first year of life, RSV is the leading source of bronchiolitis and pneumonia, and frequently results in hospitalization and recurrent wheezing or asthma. Sixty percent of infants in the US will suffer from the infection during their first winter–spring RSV season [44]. While RSV has evaded effective vaccine development in the past and even been associated with enhanced childhood disease in the setting of formalin-inactivation [45], numerous vaccine candidates are in development with target populations ranging from neonates to the elderly. A recombinant RSV vaccine is currently under evaluation in a phase II trial of pregnant women with the goal of providing neonatal protection [5]. The effectiveness of passive immunization to prevent RSV infection in young infants is supported by higher RSV cord blood antibody titers resulting in lower rates of serologic infant infection [46]. There is a paucity of data available on the incidence and impact of maternal RSV infection during pregnancy. A recent study by Falsey et al. identified the significant contribution of RSV to acute respiratory infection outside of childhood, with a 4–10% incidence among high-risk and elderly adults annually. Among the 85% of

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symptomatic individuals, 16% required hospitalization with 4% mortality and disease burden estimates similar to influenza [47]. We recently published a series of three cases of RSV infection during pregnancy, two of which required maternal mechanical ventilation and critical care due to severe respiratory compromise [48]. Given the similarities with influenza, it is very possible that the incidence and associated complications of maternal RSV infection have been underestimated. If this is in fact the case, the potential for a combined maternal and infant benefit of an efficacious RSV vaccine could be great. 5. Summary Pregnant women have unique and heightened susceptibilities to greater morbidity and mortality from a variety of bacterial and viral vaccine-preventable diseases. Currently significant attention is focused on developing vaccines for use during pregnancy with the primary goal of preventing infections in young infants. While this approach holds tremendous potential for sizable disease prevention in infants, pregnant women also have significant opportunity for disease prevention from both currently recommended and future vaccines. Maternal-child health can and will continue to be improved with ongoing efforts to prevent numerous infectious diseases in both mothers and infants. Conflict of interest The authors declare no conflicts of interest to report. Funding Dr. Swamy has received support from GlaxoSmithKline Inc., Novartis Vaccine Inc., and Novavax to conduct research funding for clinical trials in immunization. Dr. Beigi has received research funding for clinical trials in immunization from Novartis Vaccines Inc., Novavax, and Genocea BioSciences. References [1] Beigi RH. Prevention and management of influenza in pregnancy. Obstet Gynecol Clin North Am 2014;41(December (4)):535–46. [2] Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al, et al. Effectiveness of maternal influenza immunization in mothers and infants. New Engl J Med 2008;359(October (15)):1555–64. [3] Englund JA, Mbawuike IN, Hammill H, Holleman MC, Baxter BD, Glezen WP. Maternal immunization with influenza or tetanus toxoid vaccine for passive antibody protection in young infants. J Infect Dis 1993;168(September (3)):647–56. [4] Centers for Disease Control and, Prevention. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women. Advisory Committee on Immunization Practices (ACIP); 2012. p. 131–5. [5] RSV F vaccine maternal immunization study in healthy third-trimester pregnant women; 2015. https://clinicaltrials.gov/ct2/show/NCT02247726 [accessed 10.05.15]. [6] Safety and immunogenicity of a trivalent group B Streptococcus vaccine in healthy pregnant women; 2015. https://clinicaltrials.gov/ct2/show/ NCT02046148 [accessed 2.05.15]. [7] Centers for Disease Control and Prevention. Adult immunization schedules; 2015. http://www.cdc.gov/vaccines/schedules/hcp/adult.html [accessed 11.05 2015]. [8] Cantu J, Tita AT. Management of influenza in pregnancy. Am J Perinatol 2013;30(2):99–103. [9] Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148(December (11)):1094–102. [10] Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Ukoss perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. Br Med J 2011;342:d3214. [11] Yates L, Pierce M, Stephens S, Mill AC, Spark P, Kurinczuk JJ, et al. Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant. Health Technol Assess 2010;34:109–82.

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