NFID Conference: Challenges of Maternal Immunization
Day 2 of the National Foundation for Infectious Diseases Annual Conference on Vaccine Research included a focus on maternal immunization. Carol J. Baker, MD, of Baylor College of Medicine, opened the session (much to our pleasure!) with the history of evidence of the effectiveness of maternal immunization for preventing disease in newborns via passive transfer of antibodies via placenta or breastmilk. It’s generally accepted that this passive immunity, for some diseases, benefits the baby for about the first six months of life. We haven’t had a chance to look up her references, but she mentioned evidence from 1879 that showed vaccination with vaccinia prevented smallpox in infants, from 1938 showing that maternal immunization with whole-cell pertussis vaccine protected infants from pertussis complications, from 1961 showing vaccine-induced tetanus immunity transfer from mother to baby in New Guinea, and, finally, from 2011 leading to recommendation of pertussis-containing vaccine and influenza vaccine for pregnant women.
There’s much room for improvement, Baker noted, both in uptake in available vaccines in pregnant women and development of other vaccines that might be used to prevent disease in pregnant women and infants. These deficiencies prompted Baker to ask, “Why do we value risk more than benefit with pregnant women?” It’s clear that Incidents like the thalidomide tragedies in the 1960s skew the equation toward the risk side. Consequently, regulatory agencies still don’t have a licensing pathway for vaccines for pregnant women, manufacturers remain concerned about liability, and providers perceive that pregnant women are unwilling to take vaccines. Finally, Baker noted delicately that deaths of very young newborns from infectious diseases tend not to be as visible as deaths of older children, who are more integrated into and known by the community. This invisibility means that the risks of vaccine-preventable diseases in newborns tend to be underestimated by pregnant women.
Baker outlined some needs in research and surveillance that must be addressed for us to have an effective pregnancy immunization program. Large-scale efficacy trials in diverse populations are needed, bacteriologic and virologic surveillance must be strengthened in developing regions, more data is needed on barriers to vaccinating pregnant women, and rigorous safety and postmarketing surveillance will be necessary where maternal immunization is introduced.
Baker closed by saying, “We can’t await another decade of deaths and disease to have all the evidence to make policy easy. It’s time for education and implementation of good policy and a pathway to license maternal vaccines.”
Mark Sawyer, MD, of the University of California at San Diego and head of the ACIP working group on pertussis, gave an overview of pertussis in the US and the importance of vaccinating pregnant women to protect vulnerable newborns from pertussis.
The number of reported infant deaths from pertussis has increased every decade since 1980. For the most part, these deaths occur when infants are too young to be vaccinated for pertussis. (The first pertussis-containing vaccine is given at age 2 months, and infants don’t have maximum protection until they have received several more doses.)
In February, CDC issued a Morbidity and Mortality Weekly Report on pertussis that included the new recommendation that women receive Tdap in EACH pregnancy, regardless of prior immunization history or length between pregnancies. The recommendation specifies that women should take the vaccine in late second or early third trimester in order to ensure the maximum transfer of antibodies to newborn. (Sawyer noted that the data do show good transfer of antibodies to newborn, but it is not yet clear how antibody levels in mother or baby correlate to immunity.) In regard to the safety of reimmunizing women, a few European studies have shown no signal of adverse events in revaccinating nonpregnant women. Other data sources, such as vaccine manufacturer registries, VAERS, and clinical trials, have not demonstrated any signals of serious adverse events in Tdap vaccination of pregnant women.
Sawyer noted that one important result of the strategy of immunizing pregnant women for pertussis is that cases of pertussis are shifted to a later age, out of range of the known risk of severe outcomes for very young infants.
Mark C. Steinhoff, MD, from Cincinnati Children’s Hospital, talked about global aspects of prenatal influenza immunization. He conducts prospective studies in Bangladesh and Nepal on influenza vaccination of pregnant women. His results have shown reduction in influenza infection in mothers and babies, reduction in clinic visits, and positive effects in other markers related to influenza.
Interestingly, his team looked at effects on birthweight of infants exposed to influenza vaccine. They observed that giving flu vaccine to a pregnant mother improves fetal growth. Additionally, influenza vaccine in mother seems to be negatively associated with babies being small for gestational age (SGA). This is potentially very important, as there are lifetime effects of SGA birth, such as decreased IQ at age 18, decreased academic performance, and adult obesity, heart disease, stroke, and diabetes.
So, maternal influenza immunization provides benefits in three dimensions: to the mother in terms of disease prevention, to the fetus in terms of better fetal growth, and to the infant in relation to disease prevention for the first months of life.
Morven S. Edwards, MD, from Baylor College of Medicine, reviewed the prospects for group b streptococcal (GBS) vaccination in pregnant women for prevention of GBS disease in newborns. Although antibiotic prophylaxis for GBS-positive women late in pregnancy has been effective at reducing illness in newborns, Edwards regards this as an interim strategy. Antibiotic prophylaxis does not prevent later-onset GBS disease in infants, and Edwards cautions that GBS may develop antibiotic resistance. Even so, with only 27,000 cases of invasive GBS disease in US infants per year, is there a need for the vaccine?
Edwards argues there is a need: with the decline of pneumococcal meningitis due to vaccination, GBS is the leading cause of meningitis in this early newborn period. Infants who survive GBS meningitis often face lifelong moderate to severe sequelae, such as school failure, loss of digits, deafness, and intellectual impairment. What’s more, it's possible that GBS carriage by mother may be causally related to other adverse outcomes, such as stillbirth, spontaneous abortion, and perhaps even to preterm birth.
Results from the first GBS candidate vaccine were published nearly 30 years ago in the New England Journal of Medicine. The National Institutes of Health and the National Institute for Allergy and Infectious Diseases has conducted GBS vaccine trials. Dr. Baker developed and tested a GBS conjugate vaccine in healthy adults that theoretically should work, and proof of concept has been shown with a GBS conjugate vaccine in pregnant women. Edwards notes, then, that all the pieces are in place: a vaccine construct, evidence that the antibody titers are good, and evidence that the antibodies are functional.
Ten types of GBS have been identified, and a vaccine with four specific types could prevent 89% of disease. From a global perspective, you’d want to include five types of GBS to prevent 94% of disease. (Though there is very little data on neonatal GBS disease worldwide, a few studies in African countries have indicated incidence as high as 1.21 per 1000 live births).
Novartis has recently conducted a study on a trivalent conjugated GBS vaccine in 320 healthy nonpregnant Belgian women. The vaccine was well tolerated and immunogenic. The study indicated no benefit from a higher versus lower dose of antigen, from an adjuvant, or even from the second dose of vaccine. One dose of a 5 microgram nonadjuvanted vaccine was recommended for further studies. It is undergoing a Phase 2 trial in healthy pregnant women ages 18-40 and has concluded primary data collection.
Ruth Karron, MD, from Johns Hopkins Bloomberg School of Public Health, presented on respiratory syncytial virus (RSV) disease and vaccines. She opened with a slide showing many abandoned RSV candidate vaccines and the current pipeline with many vaccines in development.
The ill-fated formalin inactivated vaccine developed and tested in the 1960s illustrates one of the problems with RSV vaccine development. This vaccine was safe in toddlers, but when vaccinated infants were exposed to the disease naturally, they developed severe disease, demonstrating that the vaccine could enhance RSV disease.
Given the history with killed RSV vaccine, current vaccine approaches use replicating RSV or parts of it. MedImmune has a live attenuated RSV vaccine in development, with clinical trials to begin later this year. Subunit, fusion, and DNA vaccines are also in development by other groups.
Karron closed with side-by-side pictures of a nine-week-old infant and a nine-month-old baby. One vaccine approach, she said, isn’t going to protect both babies. We need a vaccine for the pregnant woman, and another vaccine for the older infant.
Congratulations to the speakers and to NFID for an excellent session on the challenges of maternal immunization.