ABSTRACT It is well known that exposure to one antigen can modulate the immune responses that develop following exposure to closely related antigens. It is also known that the composition of the repertoire can be skewed to favor epitopes shared between a current infection and a preceding one, a phenomenon referred to as “original antigenic sin.” It was of interest, therefore, to investigate the antibody response that develops following exposure to the malaria vaccine candidate homologue Plasmodium yoelii MSP1 ₁₉ in mice that had previously experienced malaria infection and vice versa. In this study, preexposure of mice to Plasmodium yoelii elicited native anti-MSP1 ₁₉ antibody responses, which could be boosted by vaccination with recombinant MSP1 ₁₉ . Likewise, infection of MSP1 ₁₉ -primed mice with P. yoelii led to an increase of anti-MSP1 ₁₉ antibodies. However, this increase was at the expense of antibodies to parasite determinants other than MSP1 ₁₉ . This change in the balance of antibody specificities significantly affected the ability of mice to withstand a subsequent infection. These data have particular relevance to the possible outcome of malaria vaccination for those situations where the vaccine response is suboptimal and suggest that suboptimal vaccination may in fact render the ultimate acquisition of natural immunity more difficult.