Fusing safety and efficacy: A maternal bivalent RSV prefusion F vaccine

Abstract

In this phase 3 trial, Kampmann et al.¹ demonstrated safety and efficacy of a maternal bivalent RSV prefusion F vaccine. Vaccine efficacy was achieved in reducing severe RSV-associated lower respiratory tract infections in infants at 90 and 180 days following birth.

In this phase 3, trial Kampmann et al.¹ demonstrate safety and efficacy of a maternal bivalent RSV prefusion F vaccine. Vaccine efficacy was achieved in reducing severe RSV-associated lower respiratory tract infection in infants at 90 and 180 days following birth.

Main text

Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory tract infections in infants and accounts for approximately 7% of deaths in children under the age of 1.² It is estimated that almost all children by the age of 2 will have contracted RSV, and the annual medical costs in the United States alone reach over $300 million.^3,4 Despite the tremendous health burden caused by RSV, it has taken over 60 years to successfully develop a Food and Drug Administration (FDA)-approved RSV vaccine. The first FDA-approved vaccine was recently authorized for use in adults 60 years of age or older.

There has been a long road with multiple obstacles to developing a safe and effective RSV vaccine. Two of the major obstacles in formulating an RSV vaccine are safety and long-lived immunity. Safety has been of particular concern after severe adverse events, including the death of 2 children, resulted following vaccination of children with formalin-inactivated RSV in the 1960s.⁵ Studies revealed the resulting vaccine-enhanced disease was driven by a failure to elicit a robust CD8 T cell response in combination with a non-neutralizing antibody response and a pathogenic memory CD4 T cell response.^6,7 In addition, long-lived RSV-specific immunity is difficult to achieve in infants. To overcome these obstacles, a successful vaccine would need to induce a robust, but not pathogenic, long-lasting immune response that protects infants through their first RSV season. In a recent article in the New England Journal of Medicine entitled “Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants,” Kampann et al. appear to have cracked the code to the long-standing hurdle of developing a safe RSV vaccine for protection of infants.¹

In a large phase 3, double-blinded, placebo-controlled, multi-country study, the safety and efficacy of a bivalent prefusion F (preF) vaccine was evaluated. In this 1:1 ratio study, of the maternal participants that were enrolled, 3,682 received vaccine and 3,676 received a placebo. One intramuscular injection of either a bivalent preF protein-based vaccine or a placebo was given to healthy pregnant women with a low-risk pregnancy between 24 and 36 weeks of gestation. The bivalent vaccine included 120 μg of antigen comprised of preF proteins from both major RSV substrains: A and B. Participants in the placebo group received a formulation of the vaccine without the preF proteins. Following birth, infants were monitored to evaluate efficacy of the vaccine in reducing occurrence of RSV-induced medically attended lower respiratory tract infection (MA-LRTI) and severe MA-LRTI in infants. When examining cases of RSV-associated severe MA-LRTI at 90 days following birth, 6 infants of vaccinated mothers and 33 infants of placebo mothers exhibited MA-LRTI, resulting in a vaccine efficacy of 81.8%. Within 180 days, 19 cases of RSV-associated severe MA-LRTI were reported in infants from the maternal vaccinated group and 62 cases in the maternal placebo group, lowering the efficacy to 69.4%.

When examining the success of reducing occurrence of RSV-induced MA-LRTI, the vaccine efficacy was less robust than cases of severe MA-LRTI, and the statical success criterion was not met. During the 90-day post-birth interval, 24 infants from the maternal vaccine group and 56 infants from the maternal placebo group were diagnosed with MA-LRTI, resulting in a 57.1% vaccine efficacy. A similar trend was observed within 180 days of birth in which 57 infants of vaccinated mothers and 117 infants of placebo-treated mothers were diagnosed with MA-LRTI, resulting in a vaccine efficacy of 51.3%. Vaccination with the prefusion vaccine also resulted in a moderate reduction of RSV-associated hospitalizations within 90 days after birth with 67.7% efficacy and 56.8% efficacy within 180 days. When examining occurrence of other non-RSV-associated MA-LRTI, the prefusion vaccine did not protect from or enhance the occurrence of infection by other respiratory viruses. Taken together, the data presented by Kampmann et al. validate efficacy of maternal vaccination in reducing cases of RSV-associated severe MA-LRTI.

When examining the safety profile of the bivalent preF vaccine, the vaccine demonstrated safety in mothers and infants. Maternal participants receiving the vaccine reported an increase in pain at the injection site compared with placebo. However, when examining maternal severe adverse events and side effects, there were no differences between vaccine and placebo groups. In addition, the percentages of adverse events and serious adverse events in infants were similar between infants of vaccinated and placebo-treated mothers. These critical data demonstrate that there are no notable safety concerns with this vaccine.

The study by Kampmann et al. provides an excellent foundation to confidently move forward with maternal RSV vaccinations. One of the key factors leading to the success of this vaccine is the use of the RSV F protein stabilized in the preF conformation. Prior to the fusion of RSV to the host cell membrane, there are multiple unique antigenic sites exposed on the surface of the F protein (Figure 1A). Following fusion, the F protein adopts a dramatically different confirmation where several of the antigenic sites are no longer exposed.⁸ A critical example of this is the highly immunogenic site ∅ (Figure 1B). Importantly, studies have demonstrated that most F protein-specific neutralizing antibodies in human sera are specific for the sites on the preF protein.⁹ By utilizing the preF protein in the vaccine, Kampmann et al. were likely able to enhance the immune response to RSV, leading to an effective vaccine design.

Figure 1.

Increased antigenic sites on RSV prefusion F trimer

Model diagram depicting antigenic sites on RSV F (A) prefusion and (B) postfusion timers. Sites ∅, III, and V are all present on the prefusion trimer and not the postfusion trimer. Figure generated by Laura Pietrok and created with BioRender.com.

As discussed by the authors, there will be several critical points to address in future studies. These include the safety and efficacy of the vaccine in women with high-risk pregnancies. High-risk pregnancies can lead to lower birth weights and other complications in infants that leave them more susceptible to RSV infection.¹⁰ Determining safety in these populations will be essential moving forward. In addition, the data pool from low-income countries is currently underrepresented. Vaccination will be a necessary strategy in low-income countries due to the availability and expense of RSV monoclonal antibody treatments. Future studies will also need to address the longevity of protection in infants from vaccinated mothers. Following birth, maternal antibodies wane over time. In this study by Kampmann et al., there is a slight decrease in vaccine efficacy at 180 days compared with 90 days. Future studies will need to address whether this trend continues at later time points following birth.

The data from this phase 3 clinical trial by Kampmann et al. examining the efficacy of a maternal RSV bivalent prefF vaccine are very exciting and promising. Now that a foundation for a safe and effective RSV vaccine has been established, continued research in the laboratory setting can be focused on optimizing adjuvants, antigens, and route of administration to achieve even greater efficacy moving forward.