Induction of potent antibody is the goal of many vaccines targeted against infections or cancer. Modern vaccine designs that use virus-like particles (VLP) have shown efficacy for prophylactic vaccination against virus-associated cancer in the clinic. Here we used plant viral particles (PVP), which are structurally analogous to VLP, coupled to a weak idiotypic (Id) tumour antigen, as a conjugate vaccine to induce antibody against a murine B-cell malignancy. The Id-PVP vaccine incorporates a natural adjuvant, the viral ssRNA, which acts via TLR7. It induced potent protective anti-Id antibody responses in an in vivo mouse model, superior to the “gold standard” Id vaccine, with prevalence of the IgG2a isotype. Combination with alum further increased antibody levels and maintained the IgG2a bias. Engagement of TLR7 in vivo was followed by secretion of IFN-α by plasmacytoid dendritic cells and by activation of splenic CD11chi conventional dendritic cells. The latter was apparent from up-regulation of co-stimulatory molecules and from secretion of a wide range of inflammatory cytokines and chemokines including the Th1-governing cytokine IL-12, in keeping with the IgG2a antibody isotype distribution. PVP conjugates are a novel cancer vaccine design, offering an attractive molecular form, similar to VLP, and providing T-cell help. In contrast to VLP, they also incorporate a safe “in-built” ssRNA adjuvant.
Purpose Bariatric surgery is associated with deficiencies of vitamins and minerals, and patients are routinely advised supplements postoperatively. We studied prevalence of vitamin B 12 , folate and iron deficiencies and anaemia before and after bariatric surgery over 4 years of follow-up. Materials and Methods We performed a retrospective cohort analysis of 353 people with obesity, including 257 (72.8%) women, who underwent gastric bypass (252, 71.4%) or sleeve gastrectomy (101, 28.6%) at our National Health Service bariatric centre in Northwest England. Results At baseline, mean (standard error) age was 46.0 (0.6) years, body mass index 53.1 (0.4) kg/m 2 , serum vitamin B 12 400.2 (16.4) pg/L, folate 7.7 (0.2) μg/L, iron 12.0 (0.3) μmol/L, ferritin 118.3 (8.4) μg/L and haemoglobin 137.9 (0.8) g/L. Frequency of low vitamin B 12 levels reduced from 7.5% preoperatively to 2.3% at 48 months (P < 0.038). Mean folate levels increased from baseline to 48 months by 5.3 μg/L (P < 0.001) but frequency of low folate levels increased from 4.7% preoperatively to 10.3% (P < 0.048). Ferritin levels increased from baseline to 48 months by 51.3 μg/L (P < 0.009). Frequency of low ferritin levels was greater in women (39.1%) than in men (8.9%) at baseline (P < 0.001) and throughout the study period. Haemoglobin was low in 4.6% of all patients at baseline with no significant change over the study period. Conclusion There were notable rates of haematinic insufficiencies in bariatric surgical candidates preoperatively. Our study lends further support to regular supplementation with vitamin B 12 , folic acid, and iron in people undergoing bariatric surgery.
Induction of antibody-mediated immunity against hematologic malignancies requires CD4 ؉ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4 ؉ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to "helpless" antigen silences the majority of memory IgG ؉ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM ؉ memory B cells exposed to "helpless" antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IntroductionTumor antigens are generally weakly immunogenic, and T-cell responses can be subject to tolerogenic pressure. 1 To avoid this, vaccines have been designed as conjugates of tumor antigens with immunogenic molecules, such as KLH. 2 Conjugation captures the large undamaged CD4 ϩ T-cell repertoire, providing T-cell help for the antitumor immune responses. 2,3 Idiotypic (Id) Ig-KLH vaccines aimed to suppress B-cell tumors via an anti-Id response are one example of the promise of this approach. [4][5][6] We have used a similar strategy to deliver Id fusion proteins via DNA vaccines. 7,8 The Id is composed of tumor-derived single chain Fv and is linked to the fragment C (FrC) of tetanus toxin. DNA vaccines encoding Id-FrC fusion proteins induce high levels of anti-Id antibody and protective immunity against B-cell lymphoma. 9 Continuous suppression of lymphoma cell growth probably requires maintenance of antibody levels. Although long-lived plasma cells can secrete antibody for extended periods, 10 memory B cells are also required. Survival factors for memory B cells are unclear, but antigen appears unnecessary. 11,12 For antibody responses induced by conjugate vaccines, the question of the effect of confronting memory B cells with free unconjugated "helpless" antigen, potentially derived from residual or emergent tumor, arises. In the case of Id antigen, or for carbohydrate antigens, this led to dramatic loss of memory B cells. 13 We found previously that the major fraction of the IgG component of the memory B-cell response induced by a DNA Id-FrC fusion vaccine was completely and specifically silenced by Id protein alone. 14 In contrast, Id protein coupled to FrC protein rescued and boosted the anti-Id IgG response, indicating the critical importance of CD4 ϩ T-cell help for maintenance of the memory B-cell response.We have now shown that silencing of the anti-Id IgG response by unconjugated antigen is permanent, but the surprising observation was that the IgM response appeared relatively unscathed. To assess the wider applicability of these findings and to investigate the effects of antigen on memory B cells at different maturational stages, we have used a model antigen, the well-defined hapten...
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