Maternal Immunization: Protecting Vulnerable Populations

2.1

History of Maternal Immunization

Immunization of women during pregnancy is not a new idea. Infants have long been felt to be protected against diseases that mothers had previously had. Smallpox disease has been reported to be severe in pregnant women, with case reports of severe disease in pregnant women dating back to the 19th century. Smallpox vaccination in pregnant women was first reported in an uncontrolled series in Germany in 1879, when Burkhardt reported that infants born to pregnant women who had been immunized with smallpox vaccine using “Jennerian vaccination” were not infected by smallpox vaccine during the first days following vaccination. Clinical trials of whole cell pertussis vaccine in pregnant women were conducted during the 1930s and 1940s, although antibody assays to pertussis were problematic even then. These investigators demonstrated safety in the infant, with transmission of potentially protective antibody to the infant. A description of reactions or safety in the women, some of whom received multiple doses of whole cell pertussis vaccine, was not reported. Routine immunization with multiple vaccines including influenza vaccine and polio vaccine during pregnancy was commonplace during the 1950s and 1960s in the United States, a time when polio was active and the Hong Kong influenza pandemic had demonstrated increased mortality in pregnant women. The benefits of protecting the mother against polio and influenza were perceived to be high. The safety and benefit of inactivated and live polio vaccine was demonstrated in a long-term prospective study of more than 3,000 women in the United States during that time period as well as during polio outbreaks in Finland and Israel, in which approximately 25,000 pregnant women received polio vaccine. The safety of live and inactivated polio vaccine has been described in a recent WHO review. Mass vaccination against meningococcal A disease was carried out in the 1970s in 90 million persons including pregnant women during a devastating meningococcal A outbreak in Brazil, with vaccine provided by Sanofi Pasteur. Although prospective surveillance for safety or adverse events in pregnant women and their offspring was not carried out, investigators studied maternal and cord blood levels and subsequent infant levels of antibody at 3 and 6 months of age, concluding that vaccination of the mother increased specific meningococcal antibody levels in the infants threefold compared to babies born to unvaccinated mothers, and that the antibody levels in these infants declined to ∼80% of cord levels by 3 months of age. Historically, the type and intensity of surveillance and reporting of potential adverse events associated with vaccine was less rigorous than today. As the perceived risks for pregnant women and their infants diminished, recommendations and uptake for maternal vaccination also decreased with the exception of tetanus toxoid vaccine in developing countries.

2.2

Considerations for Pregnant Women

There is currently widespread international agreement that pregnant women deserve appropriate routine medical care for their pregnancy as well as for other, nonpregnancy related conditions. Pregnant women are, in general, younger, healthier, and more likely to seek medical care than the overall female population and the availability of antenatal care facilities has been increasing over the past decades such that care is potentially available for the vast majority of women today. Societies such as the American College of Obstetrics and Gynecology advocate that women should receive treatment for medical conditions as indicated for nonpregnant women, such as antibiotics for acute infections, treatment against HIV if indicated, as well as care and prevention against important pathogens causing more frequent or severe disease in pregnant women including influenza and pertussis ( Table 10.1 ). Pregnant women should not be excluded from potentially beneficial therapies based solely on their pregnancy status, an issue that has been controversial over the past decades in areas such as clinical trials for antiretroviral therapy for HIV-infected women.

Pregnant women have mature immune systems, which are more competent than the immune systems of the fetus or neonate, and have good immune responses to protein polysaccharide, and protein-conjugate vaccines. Immune responses during pregnancy have been studied, although generally in small studies or for responses to specific pathogens such as malaria. It is known that physiologic changes during pregnancy include increased heart rate, increased stroke volume and decreased pulmonary functions overall but with an increase in oxygen carriage. These women have an increase in blood cortisol levels due to decreased clearance, and decreased cell-mediated immunity that is relatively minor but appears to predispose pregnant women to infection with listeria, tuberculosis, and toxoplasmosis. Pregnant women have a decrease in total IgG antibody due to hemodilution, which appears to return to normal shortly after delivery. Most studies indicate that the immune responses to vaccines during pregnancy are similar to those during the nonpregnant state. A recent study of inactivated influenza vaccine demonstrated that pregnant women do not have impaired humoral responses to influenza antigens and that plasmablast circulation may be even increased following immunization. Importantly, pregnant women are capable of determining benefits for themselves and their unborn child and in concert with their family, have the ability to understand the advantages of medical care including immunization and should be permitted to receive this benefit.

Rates of morbidity and mortality in pregnant women have decreased globally over the past decades due to improvements in access to prenatal care, delivery at medical centers, and improvements in medical care overall, but pregnancy still remains a time of risk for pregnant women. An estimated 289,000 women died during late pregnancy or childbirth in 2013 (WHO, UNICEF 2014). Infectious causes such as group B streptococcal infections or influenza have been documented to contribute to morbidity and infections in this population, but it is clear that better understanding of causes of maternal complications is needed. It is also known that increased access to antenatal care and delivery assistance may assist in improved outcomes in pregnant women and their infants. An important goal internationally has been improved antenatal care for pregnant women, with rates from 2010 showing that 78% of women globally receive at least one antenatal care visit (with rates ranging from 69% in the lower socioeconomic sites to 94%) in higher income locations. The accessibility of pregnant women to receive medical care can result in improvement in prenatal care, and be cost-effective for preventing neonatal deaths. Proven interventions for pregnant women include packages including education, vitamins, clean birth kits, community or clinic based delivery, and tetanus immunization prior to delivery. The contribution of maternal infections to premature onset of labor globally remains uncertain. Rates of preterm delivery, defined as childbirth occurring at less than 37 weeks gestation, has not been well documented in developing countries and identification of causes of preterm delivery in these regions is considered to be a high priority to prevent neonatal mortality.

2.3

Infants

Infants during the neonatal period, or the first 28 days of life, are most vulnerable to serious consequences related to preterm delivery, complications of delivery, and infection. It is estimated that 41% of all deaths in children under 5 years of age occur during the neonatal period. Recent global estimates show that preterm delivery is an important factor contributing to neonatal mortality, with rates of preterm delivery ranging widely from 6.4 to 17.5% around the world, with rates highest in sub-Saharan Africa. Progress in reducing childhood mortality is ongoing, with increasing vaccination of young children. The rate of decline of 5% per year in some of the highest risk countries has been documented. Nonetheless, mortality due to infection during the first months of life remain an important and potentially preventable cause of childhood deaths and innovative approaches with vaccines seem to be a promising and cost-effective measure. Strategies including multivalent vaccines, increased availability of childhood vaccination centers, and enhanced surveillance for vaccine uptake and vaccine-preventable diseases are potential implementation strategies undertaken in multiple countries.

Infant vaccine schedules vary globally, but the Expanded Programme of Immunization (EPI) schedule starts with vaccination at 6 weeks of age with subsequent doses given at 10 and 14 weeks of age. Protection from infections covered by the primary injectable vaccination series in the youngest infants is due either to preexisting maternal antibody in the infant (which generally decreases quickly over the first months of life) or to the active immune response to vaccine antigens. Typically, these vaccines consist of the pediatric diphtheria-whole cell or acellular pertussis–tetanus toxoid vaccine (DPT or DaPT), hepatitis B vaccine, Haemophilus influenzae type b conjugate (Hib) vaccine, and the multicomponent pneumococcal conjugate vaccine and protective antibody levels do not appear until at least after the second dose and more generally after the third dose. Despite tremendous progress, global coverage remains below the target of 90% coverage of infants with three doses of diphtheria–tetanus–pertussis vaccine.

Pathogens responsible for high rates of disease in the first several months of life may differ in various geographical regions. This variation may be due to standards of medical care, such as widespread utilization of clean birth techniques and adult and/or maternal immunization policies (eg, tetanus), routine individual surveillance of pregnant women [eg, HIV testing or prophylaxis for maternal Group B streptococcus (GBS) carriage], and herd immunity achieved by population-wide immunization (eg, Hib or pneumococcus). Nonetheless, common pathogens appreciated worldwide during the first months of life consist of Gram-negative bacterial infections such as Escherichia coli or Klebsiella , Gram-positive bacterial infections such as Staphylococcus pneumococcus, or GBS, parasitic infections such as malaria, and viral infections such as respiratory syncytial virus (RSV).

Although vaccine uptake in many countries is increasing overall, the timeliness of vaccine administration continues to be an issue in both developed and developing countries and thus, young infants may be unprotected against diseases such as pertussis for months between birth and the development of specific antibody following the third infant dose of vaccine. Delay in receipt of a vaccine series is common worldwide; in the United States almost half of children had some delay in receiving a DTaP vaccine dose and 16% were delayed in vaccine receipt for more than 6 months in the first 2 years of life. A longitudinal study in Ghana reported that while coverage for three doses of DTP was 95% at 12 months, only 10% of infants were vaccinated within 1 week of the scheduled time of 14 weeks; and the median delay for the third dose of DTP was 4 weeks.

2.4

Transplacental Antibody Transfer

Maternal IgG antibody is actively transported across the placental using specific receptors. Active transport of maternal IgG occurs primarily after 32 weeks gestation; infants born before this time have low levels of maternal antibody. By the time of delivery of a full-term infant in a healthy mother, the level of IgG is generally higher in the infant than the mother due to this active transport. Multiple factors influence the transfer of maternal IgG during pregnancy, including placental integrity, total maternal IgG concentration, IgG subtype, and if vaccine is administered, the timing of vaccination relative to delivery. The presence of maternal infection with HIV or malaria can reduce antibody transfer by reducing the ability of the placenta to transport IgG through impairment of Fc receptor function. The impact of HIV infection in reducing neonatal antibody titers to Bordetella pertussis , tetanus, and pneumococcal antibodies in South Africa has been shown to lead to a reduction in antibody levels of 15–40%. Higher levels of total maternal IgG may also reduce transfer of antigen-specific IgG by competitive binding to placental Fc receptors.

The maternal transfer of IgG subtypes varies. IgG ₁ , which is induced primary by protein antigens such as tetanus toxoid, is most efficiently transferred while IgG ₂ , induced by polysaccharide antigens such as pneumococcus, is least efficiently transferred. Infant antibody titers rise approximately 2 weeks after maternal vaccination. In a study of Hib conjugate vaccine, transmission of antibodies was greatest in mothers vaccinated more than 4 weeks before delivery. Vaccination with a conjugate vaccine at between 28 and 32 weeks gestation may optimize the amount of disease-specific IgG present at time of delivery and ensure the greatest period of protection for neonates. For diseases where seasonality plays an important role such as influenza, and where there is substantial risk to the pregnant woman and fetus as well as the infant, the US Advisory Committee on Immunization Practices (ACIP) recommends vaccination at the beginning of the seasonal epidemic.

Maternal immunization with Hib vaccine was studied in the 1990s ( Table 10.2 ). Epidemiological evaluation of reduction of Hib disease due to decreased carriage and herd immunity provided by pediatric immunization with the extremely effective conjugate Hib vaccine makes maternal immunization less likely to benefit infants. Nonetheless, maternal Hib vaccine studies have demonstrated the importance of timing of maternal vaccine, differential rates of IgG subtype antibody transfer, the lack of neonatal or infant priming by maternal immunization with protein or protein-conjugate vaccines, and the higher rates of antibody transferred to the fetus when immunization takes place during rather than prior to pregnancy ( Table 10.2 ).

2.5

Why Immunize a Pregnant Woman?

Several vaccines are currently recommended for use in pregnant women ( Table 10.1 ). Immunization during pregnancy has been utilized for more than 50 years to prevent tetanus disease in mothers and infants, a disease that was responsible for up to 30% of deaths in developing countries up to the middle of the 20th century. Ongoing campaigns against tetanus lead by UNICEF, WHO, and other organizations have resulted in the eradication of neonatal tetanus from many countries, and the Western Hemisphere ( Fig. 10.1 ). Experience from the tetanus vaccine campaigns have shown that immunization during pregnancy is feasible, as it may be integrated into with routine prenatal care. This approach has also shown that immunization during pregnancy has the potential to protect two individuals—the mother and the infant—during a vulnerable period of life at a minimal cost. Furthermore, pregnant women are increasingly accessible to medical care. Access to antenatal care, a Millenium Development Goal of the United Nations, is increasing and becoming more widely available even in the lowest income countries and this access, which typically occurs during the last months of pregnancy, provides an opportunity to provide vaccine as well as other health care to these women. Finally, maternal immunization strategies are far safer and less expensive than the administration of exogenous immunoglobulin products to the infant. The use of monoclonal antibodies against RSV, for example, in preterm infants has been effective in reducing RSV-related lower respiratory tract disease but at a cost exceeding resources in most settings.