Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

Antibody persistence 3 years after immunization of adolescents with quadrivalent meningococcal conjugate vaccine.

BACKGROUND: A quadrivalent meningococcal conjugate vaccine (MCV-4) is recommended for United States teenagers. The duration of protective immunity is unknown. We investigated serum antibody persistence 3 years after vaccination of adolescents. METHODS: Serum samples from participants of a randomized trial who had received MCV-4 (n=52) or polysaccharide vaccine (MPSV-4; n=48) and from unvaccinated controls (n=60) were assayed for serogroups C, W-135, and Y anticapsular antibody concentrations by use of a radioantigen binding assay and for bactericidal activity (in a human complement assay) and passive protection against serogroup C bacteremia in an infant rat model. RESULTS: A higher proportion of participants in the vaccine groups had protective bactericidal titers (> or =1 : 4), compared with that in the control group (for MCV-4 recipients vs. controls, P<.01; for MPSV-4 recipients vs. controls, P< or =.06). More MCV-4 recipients had W-135 bactericidal titers > or =1 : 4 than did MPSV-4 recipients (P=.01). More MCV-4 recipients had passive protective activity against serogroup C bacteremia than did MPSV-4 recipients (76% vs. 49%; P<.01). The differences in protective activity were largest between participants in the vaccine groups with bactericidal titers <1 : 4 (63% protective in MCV-4 recipients vs. 31% protective in MPSV-4 recipients; P=.01). CONCLUSIONS: Compared with MPSV-4, MCV-4 elicited greater persistence of antibody activity against serogroups C and W-135 at 3 years after vaccination in adolescents. On the basis of passive protection data in an infant rat model, bactericidal titers > or =1 : 4 underestimate protective immunity.

Sequential immunization with vesicles prepared from heterologous Neisseria meningitidis strains elicits broadly protective serum antibodies to group B strains.

The capsular polysaccharide of Neisseria meningitidis group B is an autoantigen, whereas noncapsular antigens are highly variable. These factors present formidable challenges for development of a broadly protective and safe group B vaccine. Mice and guinea pigs were sequentially immunized with three doses of micovesicles or outer membrane vesicles prepared from three meningococcal strains that were each antigenically heterologous with respect to the two major porin proteins, PorA and PorB, and the group capsular polysaccharide. The resulting antisera conferred passive protection against meningococcal group B bacteremia in infant rats and elicited complement-mediated bactericidal activity against genetically diverse group B strains that were either homologous or heterologous with respect to PorA of the strains used to prepare the vaccine. By using knockout strains, a portion of the bactericidal antibody was directed against the highly conserved protein, neisserial surface protein A (NspA). Further, an anti-NspA monoclonal antibody elicited by the sequential immunization was highly bactericidal against strains that were previously shown to be resistant to bacteriolysis by anti-NspA antibodies produced by immunization with recombinant NspA. Sequential immunization with heterologous vesicle preparations offers a novel approach to eliciting broadly protective immunity against N. meningitidis strains. An NspA-based vaccine prepared from protein expressed by Neisseria also may be more effective than the corresponding recombinant protein made in Escherichia coli.