Targeting TLRs Expands the Antibody Repertoire in Response to a Malaria Vaccine

The use of TLR agonists in vaccination broadens the range of polymorphic variants against which the antibodies can be effective. Help! Sometimes one very talented athlete can carry a team to a championship. Yet, not even the best athletes can reach their full potential without the support of their teammates. Similarly, successful vaccines require strong and specific pathogen-derived antigens, but frequently, one of these essential players is not multitalented enough to elicit a protective immune response. To do so, these stars require help—which comes in the form of adjuvants. Whereas specific antigens induce a slower but pathogen-restricted immune response, adjuvants activate the faster but more general innate immune system. The addition of adjuvants to vaccine formulations is known to improve the quality, strength, and duration of the immune response by somewhat nebulous mechanisms. Now, Wiley et al. use massively parallel sequencing to quantify the immune response to a malarial antigen and find that a little help from an adjuvant results in added antibody diversity. The authors showed that adding a Toll-like receptor 4 agonist, which turns on a pattern-recognition receptor that activates innate immune cells, to a commonly used oil-in-water adjuvant in an antimalaria vaccine formulation greatly increased the diversity of antibodies made in response to the vaccine. These antibodies were better able to neutralize and could respond to more variants of the antigen. Therefore, in the context of an infection, these adjuvanted vaccines should be able to successfully fight more strains of a pathogen. What’s more, the sequencing method used by Wiley et al. should be broadly applicable to the characterization of immune responses to other vaccines and to infections, thus leading to improvements in the detection, diagnosis, and treatment of various diseases. Furthermore, this strategy can be used to scout out adjuvants that make the best teammates for pathogen-specific antigens in vaccine formulations. Vaccination with an isolated antigen is frequently not sufficient to elicit a protective immune response. The addition of adjuvants to the antigen can increase the magnitude and breadth of the response generated, but quantification of this increase as a function of adjuvant has been intractable. We have directly determined the variation of the immunoglobulin G variable-chain repertoire of an entire organism as a function of vaccination. Using the well-established Plasmodium vivax antigen, PvRII, and massively parallel sequencing, we showed that the use of a Toll-like receptor (TLR) agonist in the vaccine formulation increased the diversity of the variable region sequences in comparison to the use of an oil-in-water emulsion adjuvant alone. Moreover, increased variable domain diversity in response to the use of TLR agonist–based adjuvants correlated with improved antigen neutralization. The use of TLR agonists also broadened the range of polymorphic variants against which these antibodies could be effective. In addition, a peptide microarray demonstrated that inclusion of adjuvants changed the profile of linear epitopes from PvRII that were recognized by serum from immunized animals. The results of these studies have broad implications for vaccine design—they may enable tailored adjuvants that elicit the broad spectrum of antibodies required to neutralize drifted and polymorphic pathogen strains as well as provide a method for rapid determination of correlates of adjuvant-induced humoral immunity.