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BACKGROUND. VRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry. METHODS. Healthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants. RESULTS. Median VRC01 levels were quantifiable in serum (96.2 [micro]g/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo [HIV-1.sub.Bal26] challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); [HIV-1.sub.Du422.1] infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). [HIV-1.sub.Bal26] infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003). CONCLUSION. Intravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy. FUNDING. National Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation., Introduction In 2019, 1.7 million people were newly infected with HIV-1 (1), in nearly all regions of the world, even in countries with access to the latest prevention toolkit. Clearly, [...]

BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 x NYVAC-B followed by 1 x [10.sup.10] PFU rAd5 (NYVAC/[Ad5.sub.hi]); 1 x [10.sup.8] PFU rAd5 followed by 2 x NYVAC-B ([Ad5.sub.lo]/NYVAC); 1 x [10.sup.9] PFU rAd5 followed by 2 x NYVAC-B ([Ad5.sub.med]/NYVAC); 1 x [10.sup.10] PFU rAd5 followed by 2 x NYVAC-B ([Ad5.sub.hi]/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. [CD4.sup.+] T cell response rates ranged from 42.9% to 93.3%. NYVAC/[Ad5.sub.hi] response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. [CD8.sup.+] T cell response rates ranged from 65.5% to 85.7%. NYVAC/[Ad5.sub.hi] magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/[Ad5.sub.hi] and 21.4%, 84.6%, and 100% for [Ad5.sub.lo]/NYVAC, [Ad5.sub.med]/NYVAC, and [Ad5.sub.hi]/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for [Ad5.sub.med]/NYVAC and [Ad5.sub.hi]/NYVAC than for NYVAC/[Ad5.sub.hi]. CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883. FUNDING. NIAID, NIH UM1AI068618, AI068635, AI068614, and AI069443., Introduction An effective prophylactic HIV vaccine remains a major global health target, especially in developing countries bearing the brunt of the 2.5 million new infections estimated in 2011 (1). Recent [...]