Serologic studies have demonstrated that Tdap vaccine induces high anti-pertussis antibodies when administered during pregnancy, but that the half-life of those antibodies is brief. When Tdap is given during pregnancy, and the infant is born at or near term, the antibody transfer to the infant is expected to provide passive protection for several months. Maternal immunization during pregnancy thereby reduces the risk that the mother will develop pertussis and transmit it to her newborn, while at the same time allows a degree of passive immunoprotection to the infant during the most vulnerable period of life. Active immunization against pertussis in the infant begins between 6-8 weeks of age.
Another infection that is exceedingly common during the first several months of life is respiratory syncytial virus (RSV). RSV remains the most common reason for infant hospitalization in the United States and other developed countries. The source of the virus can be any other person with a mild or moderate respiratory tract infection as the virus is ubiquitous, and can re-infect individuals throughout their lifetime. The first infection, however, is the worst. It is estimated that between 3% and 4% of the U.S. birth cohort is hospitalized with RSV. With a U.S. birth cohort of about 4 million, the result is 120,000-160,000 infant admissions annually.
The RSV epidemic is seasonal, fairly predictable, and dreaded by primary care pediatricians and hospitalists alike. Lower respiratory tract infection with RSV, in the form of RSV bronchiolitis, presents all too commonly in the young infant with cough, coryza, tachypnea, and wheezing. When the work of breathing increases, and the cough symptoms predominate, the infant is unable to feed efficiently. Hospitalizations may be for dehydration, concerns for impending respiratory failure, or for the administration of supplemental oxygen or other respiratory support. No specific therapeutic interventions reliably reduce the symptoms or the length of hospital stay, nor do they reduce the possibility that intensive care with mechanical ventilation may be required. Treatments are only supportive. An effective vaccine remains elusive.
All other common infections that once resulted in high rates of hospitalization in the first year of life are now substantially reduced through vaccination. Why not this one? The development of a safe and effective vaccine to prevent infant RSV infection or to reduce RSV-associated hospitalizations is especially challenging for multiple reasons.
Some of these reasons have met with substantial advances quite recently, including the discovery of antigen structures needed to induce neutralizing antibody responses. There also are challenges specific to the infant group we need most to protect. Infant RSV infection itself confers only modest protection against subsequent infection. Repeated infections over time are necessary for protection against illness when re-exposed. A vaccine that is able to induce a response similar to natural infection would therefore require multiple doses, presumably over time (the so called ‘primary series’) before a substantial clinical benefit would be expected. This is particularly important because most RSV-associated hospitalizations occur during the first several months of life, reducing the timeline for which a protective vaccine series could be administered.
The challenges are parallel to the issues described earlier for protection against both influenza and pertussis. Infant protection against both of these infections are now addressed, at least to start with, by vaccinating the mother during her pregnancy. In the infant, the pertussis vaccine primary series is then initiated between 6 and 8 weeks of age, and the influenza series initiated at 6 months of age. It is the passive protection, in the form of transplacental maternal antibody, that offers the interim protection during the highest-risk first months of life.
For infants at very high risk of serious RSV infection, passive antibody protection is already administered in the form of the pharmacobiologic medication palivizumab. Its half-life dictates monthly injections for those eligible, and its cost precludes its use for any but the highest risk infants (those born prematurely, and those with chronic lung disease and/or congenital heart disease). This strategy, however, has proven effective in preventing RSV-associated hospitalization in every group in which it has been studied. This “proof of concept” strongly suggests that if the right RSV vaccine is given to women during pregnancy to induce a robust neutralizing anti-RSV antibody response, and that antibody is transferred to the fetus prior to birth, the newborn will benefit from protection against RSV for a period of time.
Several questions emerge. If RSV is ubiquitous, and can re-infect individuals throughout their lifetime, then some women will be infected during their pregnancy. Do their infants benefit? As a re-infection, the maternal symptoms would be expected to be mild, but the infection could boost the women’s natural immunity with a robust anamnestic antibody response. This possibility has not been studied systematically, but might help to explain why some healthy term infants exposed to RSV develop little or no symptoms, while others (mothers who have not recently had a natural RSV infection) develop severe illness requiring hospitalization.