Antibody affinity maturation and respiratory syncytial virus disease

To the Editor:

The mouse immunization experiments reported in Delgado et al.¹ support the hypothesis that failure to elicit affinity-matured, neutralizing antibodies contributed to disease enhancement after immunization of children with a formalin-inactivated respiratory syncytial virus vaccine candidate (FI-RSV) in the 1960s. However, the authors' assertion that lack of protection by FI-RSV was “not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes” is not justified by the data presented. On the contrary, Figure 3h of their paper presents data showing that neutralizing epitopes are largely absent from FI-RSV, presumably as a result of formalin inactivation or another insult during vaccine preparation. Their conclusion that antibody avidity alone was responsible for disease enhancement predicts that disease enhancement by FI-RSV could be overcome by stimulating affinity maturation with a Toll-like receptor (TLR) agonist. However, they did not report this key test of their proposed explanation for disease enhancement by FI-RSV in the paper. Delgado et al. do show enhanced protective efficacy of ultraviolet light–inactivated RSV upon formulation with TLR agonists, and other investigators have reported that formulating FI-RSV with monophosphoryl lipid A, a TLR4 agonist, reduces vaccine-induced immunopathology in immunized and challenged cotton rats². The observations by Delgado et al.¹ and in the literature indicate that a protective RSV vaccine must both present neutralizing epitopes and elicit affinity-matured antibodies recognizing those epitopes.

It stands to reason that vaccine-mediated disease enhancement can occur only if a vaccine fails to elicit high-affinity neutralizing antibodies that prevent infection. However, contrary to the authors'¹ statement that “this study explains why the inactivated RSV vaccine did not protect the children and subsequently led to severe disease,” their data do not explain why an RSV vaccine that fails to block infection actually enhances subsequent disease. TLR agonists drive more than just affinity maturation. They also enhance neutralizing antibody titers and breadth, promote isotype switching and alter the balance of T helper type 1 and T helper type 2 responses. Thus, these agonists might block disease enhancement by multiple mechanisms. The requirement for an RSV vaccine to elicit high-affinity neutralizing antibodies and the utility of TLR agonists are points well taken, but future vaccines must also present native RSV structures.