With respiratory syncytial virus vaccine development for infants and children proceeding slowly, therapeutic developers have focused on passive immunity
Each year, up to 100,0001 children worldwide lose their lives due to complications of respiratory syncytial virus (RSV). Although vaccines have the power to prevent serious infections, hospitalizations, and deaths, the odyssey of developing a safe and effective RSV vaccine for vulnerable populations, especially children, has been marred by discouraging clinical failures.
The approval of 2 RSV vaccines from GlaxoSmithKline and Pfizer for adults 60 years of age and over offers new hope. However, these new vaccines are unsuitable for infants and young children, highlighting the ongoing need for vaccines to safeguard this vulnerable group.
RSV is a highly contagious respiratory virus and ranks as the second-leading cause of infant mortality worldwide, with more than 99% of RSV-related deaths occurring in low to middle-income countries.2 In the United States, RSV is the leading cause of infant hospitalizations, with an estimated 58,000 to 80,0003 children under 5 years of age hospitalized annually and an estimated 100 to 300 deaths.4
The journey to an RSV vaccine for infants and children began in the 1960s when development resulted in grave failures. Instead of providing protection, an experimental formalin-inactivated RSV vaccine resulted in enhanced RSV disease (ERD)2 among vaccinated infants who were subsequently exposed to RSV. Vaccinated children fared worse than unvaccinated children in the clinical study, including the deaths of 2 vaccinated children. Without an explanation for why ERD occurred, RSV vaccine development came to a halt.
Decades later, scientists developed a better understanding of ERD. Vaccine approaches that use antigens that are not produced intracellularly, such as inactivated virus or protein subunit vaccines, can elicit an unbalanced immune response. When such antigens2 are processed and presented, helper T cells can be activated without sufficient activation of killer T cells, resulting in a biased immune response that favors antibody production and triggers a harmful immune response. This response drives the expression of potent cytokines, leading to ERD.
With this improved understanding of the mechanisms driving ERD, developers have cautiously advanced new RSV vaccines for infants and children. Renewed excitement focused on a vaccine developed5 by MedImmune in the 2000s that used bovine parainfluenza virus 3 (PIV3) as a live vaccine vector.
The vaccine safely elicited an anti-RSV immune response in children who had not had prior exposure to RSV but unfortunately was later found to be genetically unstable, such that the vaccine would stop expressing the RSV antigen. Half of the vaccinated children did not develop robust anti-RSV immune responses, and the program was ultimately discontinued. However, Medimmune’s breakthrough work showed that a live, replicating viral vector can be a safe and promising approach to RSV vaccines for infants and children.
With RSV vaccine development for infants and children proceeding slowly, therapeutic developers have focused on passive immunity. Just this summer, long-acting RSV monoclonal antibodies were approved for infants.6
The Centers for Disease Control and Prevention (CDC) recently recommended their routine use, yet their cost may limit distribution in low- and middle-income countries that are most affected by RSV. In addition, a recently approved maternal vaccine is designed to produce antibodies passed from mother to infant, protecting against severe RSV infection in the early months of life.8 Both of these approaches, assuming the monoclonal antibodies are dosed at birth, are expected to protect infants for about the first 6 months of life.
However, 6 months of protection may not be adequate for babies born at or before the beginning of an RSV season, which is typically 7 months long, to say nothing of subsequent RSV seasons. An RSV vaccine that extends protection beyond 6 months is still needed.
What would an ideal vaccine for infants look like?First and most importantly, the vaccine must not trigger ERD. Beyond that, an ideal vaccine would induce a robust and durable immune response lasting 2 or more years, reduce symptoms, prevent infection and transmission, have limited adverse effects, and elicit a strong response even in the presence of maternal or exogenously administered RSV monoclonal antibodies.
Vaccine developers are pursuing various strategies for infant RSV immunization, including Moderna’s mRNA vaccine; Sanofi’s, Meissa’s, and Codagenix’s live-attenuated vaccines; and Blue Lake Biotechnology’s live PIV5-vectored vaccine. It has been hypothesized that intracellular processing of vaccine antigens enables a more balanced immune response that avoids triggering RSV-associated ERD, so mRNA vaccines may avoid this problem, but this awaits clinical validation. On the other hand, live vaccines can stimulate infants’ immune systems against RSV without ERD risk. Clinical studies of live-attenuated RSV vaccines, including MedImmune’s efforts, suggest they are safe in this regard.
The live recombinant PIV5-based vaccine is derived from a modified canine virus that has been used in intranasal kennel cough vaccines for over 50 years. Dogs can shed PIV5 after vaccination for up to 5 days, during which time they potentially expose their owners and other humans.
Yet after 5 decades of use and potentially hundreds of millions of human exposures, PIV5 has not been proven to cause any human disease. PIV5-vectored vaccines have so far been safe and immunogenic in humans in clinical trials, which are currently enrolling infants, young children, and elderly subjects. It is also encouraging that the PIV5-based RSV vaccine has generated robust immune responses in adults who are RSV-positive, suggesting that the vaccine may be able to overcome pre-existing neutralizing RSV antibodies.
The PIV-based RSV vaccine is designed to be administered intranasally, thus stimulating mucosal immunity and triggering the development of IgA antibodies9 that defend against RSV at the site of viral entry. Intranasal administration may provide a unique advantage in protecting individuals, potentially blocking transmission, and reducing disease spread—an elusive feat for current injectable vaccine technologies. Combining the benefits of intranasal delivery and a live recombinant virus, this approach holds promise in providing broad applicability, a safe, balanced, and potent immune response, and protecting infants and children against RSV infection—all while being needle-free.
Considering the potential offered by live recombinant vaccines administered through intranasal delivery, the quest for a safe and effective vaccine against RSV gains momentum as the urgent need remains for infants and young children. Despite past setbacks, strategies such as monoclonal antibodies, maternal vaccines, live recombinant vaccines, and mRNA vaccines offer hope.
However, although anti-RSV antibodies can reduce the symptoms of RSV infection, we must achieve active immunity and prevent infection and transmission to truly protect infants and young children. It is important to recognize the remarkable strides being made in RSV vaccine development. By harnessing the power of innovative approaches, we can protect this vulnerable group and pave the way for a healthier future for our children.
About the Author
Biao He, PhD, founder and CEO, Blue Lake Biotechnology.