Vaccines against Respiratory Viral Pathogens for Use in Neonates: Opportunities and Challenges

Abstract

The first six months of life reflects a time of high susceptibility to severe disease following respiratory virus infection. While this could be significantly improved by immunization, current vaccines are not approved for use in these very young individuals. This is the result of the combined effects of poor immune responsiveness and safety concerns regarding the use of live attenuated vaccines or potent adjuvants in this population. Vaccines to effectively combat respiratory viral infection would ideally result in robust CD4+ and CD8+ T cell responses as well high affinity antibody. Inclusion of TLR agonists or single cycle viruses are attractive approaches for provision of signals that can act as potent stimulators of DC maturation as well as direct activators of T and/or B cells. Here we discuss the challenges associated with generation of a robust immune response in neonates and the potential for adjuvants to overcome these obstacles.

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

“…For example, recruitment of T cell help to B cells is hampered as a result of low MHC II and reduced antigen processing and presentation [11]. In addition, decreased dendritic cell maturation contributes to poor CD4 + T cell generation necessary to support antibody responses [4, 12, 13]. Finally, neonates demonstrate impairment in the CD40-CD40L pathway which plays a critical role in regulating B cells differentiation and function [14, 15].…”

Determinants of early life immune responses to RSV infection

“…However, infants are known to have significantly diminished antibody responses compared to adults and several intrinsic and extrinsic B cell limitations have been described [7,34,35]. For the first several months of life, B cells have a limited ability to promote somatic mutation required for affinity maturation.…”

“…Nearly all infant vaccines, including thehepatitis B vaccine first administered at birth, rely on repeated exposure to generate sufficiently protective memory responses. BCG, a potent immune stimulator given to infants outside of the US, can stimulate immune responses in infants similar to those of adults after a single dose [34]. The ability of infants to respond to vaccination appears to depend on nature and strength of the stimulus, with the responses to different vaccines or vaccine components in infants approaching those of adults at different ages[18,34].…”

“…BCG, a potent immune stimulator given to infants outside of the US, can stimulate immune responses in infants similar to those of adults after a single dose [34]. The ability of infants to respond to vaccination appears to depend on nature and strength of the stimulus, with the responses to different vaccines or vaccine components in infants approaching those of adults at different ages[18,34]. Immunosuppressive features of infant immunity, as well as the inherent ability of the lung itself to negatively regulate effector cell function [34], make the choice of antigen and the context in which it is administered critical choices in the design of infant vaccines against RSV.…”

“…For induction of robust T and B cell responses and high-affinity antibodies, the inclusion of TLR agonists is one attractive approach[34]. Targeting DCs, particularly DC populations located in the lung, is critical to promoting the generation of more mature adaptive responses (Figure 1).…”