Given this background the study of Scherer et

Given this background, the study of Scherer et al. reported in this issue () is of considerable interest, because it provides the first in-depth analysis of the change in the VLP/virion antibody repertoire in individual women who were naturally infected by HPV, and who are then vaccinated with VLPs. The authors used state-of-the-art technologies to isolate circulating virion-specific memory B cells (Bmem). They then sequence the antibody-encoding genes, and finally clone, express, and functionally test the RGDfK they encode. The primary, and perhaps surprising, conclusion of the study is that the antibodies in the Bmem repertoire after natural infection are predominantly low avidity and non-neutralizing. In contrast, the Bmem repertoire in women who were boosted by a single dose of Gardasil mostly contains higher avidity and neutralizing antibodies. The authors previously reported that women who were seronegative at the time of vaccination also generated mostly neutralizing antibodies (). The findings support the possibility that women who are seropositive due to infection might nonetheless benefit from VLP vaccination. However, it is important to note that the authors appropriately caution that they conducted “an exploratory, unblinded pilot study”, and public health policy should not be unduly influenced by the tentative conclusions drawn from a study of five individuals. Further studies are warranted. This study highlights several important questions in this field. The first question is why the antibody response to infection and vaccination appear to be so qualitatively different. Given the small number of virion-binding Bmem identified after infection, it is difficult to eliminate the possibility of confounding due to the inclusion of Bmem that were actually specific for another antigen but sufficiently cross-reactive toward VLPs to be isolated using the procedures employed. Arguing against this scenario is the fact that the same isolation procedure identified mostly high avidity and neutralizing clones after vaccination. A far more attractive possibility is that the difference reflects the very different context in which the antigen is presented to the immune system after infection versus vaccination. With intramuscular vaccination, the antigen is delivered at high dose to the systemic immune system in a pro-inflammatory context, due to the presence of the adjuvant. This type of exposure of a repetitive particulate antigen generally induces a strong germinal center reaction in the draining lymph nodes that in turn generates hypersomatic mutations in the variable domains of the immunoglobulin genes and ultimately high avidity antibodies (). In contrast, productive HPV infections are limited to epithelial surfaces and are largely non-inflammatory. In addition, L1 protein is expressed and viruses are produced only in the most superficial epithelial layers. Therefore, during infection, L1 will usually be exposed to the immune system at very low dose and predominately in a non-inflammatory setting, a situation that would seem unlikely to induce a long lived germinal center reaction (). Antibodies generated in this context would be expected to have the low avidity characteristics observed in the virion antibodies detected after infection. However, this otherwise attractive explanation is difficult to reconcile with the authors\' finding that the number of somatic mutations in the L1 antibodies sequenced was similar before and after vaccination. Clearly there are aspects of the B cell responses to virus-like antigens, particularly in a low dose mucosal context, that require further investigation.
Pneumococcal meningitis is a relevant world-wide problem with ~1.000,000 cases within the last 20years, 80,000 alone in 2009 (Global Healthy Observatory Data of the World Health Organization). Pneumococcal meningitis causes the highest mortality rates of all meningitis-causing bacterial pathogens and the highest rates of severe disabling neurological sequelae ().