Immune Monitoring Reveals Fusion Peptide Priming to Imprint Cross-Clade HIV-Neutralizing Responses with a Characteristic Early B Cell Signature.

The HIV fusion peptide (FP) is a promising vaccine target. FP-directed monoclonal antibodies from vaccinated macaques have been identified that neutralize up to ∼60% of HIV strains; these vaccinations, however, have involved ∼1 year with an extended neutralization-eclipse phase without measurable serum neutralization. Here, in 32 macaques, we test seven vaccination regimens, each comprising multiple immunizations of FP-carrier conjugates and HIV envelope (Env) trimers. Comparisons of vaccine regimens reveal FP-carrier conjugates to imprint cross-clade neutralizing responses and a cocktail of FP conjugate and Env trimer to elicit the earliest broad responses. We identify a signature, appearing as early as week 6 and involving the frequency of B cells recognizing both FP and Env trimer, predictive of vaccine-elicited breadth ∼1 year later. Immune monitoring of B cells in response to vaccination can thus enable vaccine insights even in the absence of serum neutralization, here identifying FP imprinting, cocktail approach, and early signature as means to improve FP-directed vaccine responses.

Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen.

The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) - when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) - to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rTTHC; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment.

Environmental tobacco smoke and cardiometabolic risk in young children: results from a survey in south-west Germany.

AIMS: We explored the association between exposure to environmental tobacco smoke (ETS) and various cardiometabolic biomarkers in 10-year-old children. METHODS AND RESULTS: A population-based cross-sectional study was carried out. Data on ETS exposure and potential confounders were collected by parental questionnaire. Adiponectin, leptin, markers of inflammation, apolipoproteins (apo) AI and B, and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) were measured. Linear and logistic regression models were applied using the 90th percentile as a cut-off point except for adiponectin and apoAI (10th percentile). In linear models, ETS exposure was significantly associated with increasing plasma concentrations of leptin, C-reactive protein, fibrinogen, interleukin (IL)-6, and Lp-PLA(2). When compared with none, ETS exposure of more than 10 cigarettes per day was associated with elevated concentrations of leptin (OR 6.40; 95% CI, 2.67-15.39), C-reactive protein (OR 3.17; 95% CI, 1.31-7.68), Lp-PLA(2) (OR 2.97 95% CI, 1.32-6.68), low adiponectin (OR 2.69; 95% CI, 1.10-6.57), and low apoAI (OR 4.48; 95% CI, 2.16-10.85). Increasing dose of ETS exposure was related to an increasing number of abnormal cardiometabolic markers. CONCLUSION: Among children, ETS exposure was associated with a low-grade inflammatory response and altered markers of lipid metabolism, which may initiate atherosclerosis in early life. However, longitudinal studies are necessary to determine the potential causal relevance of these associations.