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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination. [Display omitted] • Designed a human PCSK9 mimic with no consecutive 9 residues of any human protein • Immunization with the PCSK9 mimic significantly reduced cholesterol and LDL levels • Vaccine-induced antibodies altered PCSK9 half-life, confounding vaccine impact Proprotein convertase subtilisin/kexin type 9 (PCSK9) controls cholesterol homeostasis. To assess the feasibility of a PCSK9-based heart attack vaccine, Zhang et al. create a PCSK9 mimic and demonstrate in mice and NHPs its ability to significantly reduce cholesterol. Unexpectedly, the vaccine-induced antibodies also altered the PCSK9 half-life, blunting vaccine impact. [ABSTRACT FROM AUTHOR]

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. • Immunization in 32 rhesus macaques reveals FP priming to imprint cross-clade responses • Identifying an early B cell signature predictive of vaccine outcome • Priming with a cocktail of FP and trimer elicits the earliest neutralizing responses • B cell immune monitoring enables vaccine insights, even without serum neutralization Immune monitoring of B cells in response to vaccination can enable early insights, even in the absence of serum neutralization. Cheng et al. observe an early B cell signature in NHPs predictive of the vaccine outcome, with priming of HIV FP imprinting cross-clade neutralizing FP-directed vaccine responses. [ABSTRACT FROM AUTHOR]