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Despite widespread immunization with Bacille-Calmette-Guerin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing. Author summary: Despite over 100 years of vaccination with the current tuberculosis (TB) vaccine, Bacille Calmette-Guérin (BCG), TB remains the world's leading infectious killer. Although BCG is effective in some settings, it has been overmatched as a tool to curb the global TB pandemic; a better vaccine is needed. Many TB vaccine candidates are being developed, but human TB vaccine trials are costly and take years to complete. The most promising candidates must be identified and prioritized, but existing animal models for TB vaccine testing poorly predict efficacy in humans. Recently we described an improved mouse TB model that uses an ultra-low dose (ULD) challenge of 1–3 Mycobacterium tuberculosis (Mtb) bacteria, which more closely reflects a human inoculum. Here we use the ULD model to examine protection provided by BCG vaccination. Compared to conventional dose Mtb infection, we show that BCG vaccination in the ULD model leads to longer lasting protection, blocks dissemination from one lung to the other, and prevents detectable infection in a small percentage of mice. Overall, we show that the ULD model can measure unique aspects of protection that cannot be assessed in existing models and could provide an improved platform for prioritizing TB vaccine candidates. [ABSTRACT FROM AUTHOR]

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection. Author summary: The RV144 vaccine efficacy trial showed a reduction in HIV-1 infections that associated with binding antibody responses to the Envelope (Env) V1V2 loops but precise mechanisms remain unclear. To evaluate the effect of vaccine priming, we performed a systems serology analysis in 37 vaccine and 63 placebo recipients 6, 12 and 36 months after HIV-1 breakthrough infections. Vaccinees were characterized by strong V1V2-specific antibody responses synergized with V1V2-specific ADCP responses, whereas placebo recipients had stronger IgG3 and gp120-specific responses. The strongest distinguishing feature for vaccinees was IgG4 responses. RV144 vaccination enhanced Fc-mediated effector functions but limited the development of broadly neutralizing antibodies post-infection, which were found in eight placebo recipients but no vaccinee. These data show that RV144 vaccination primed B cells towards specific binding and functional antibody responses, with differences between groups still manifest three years after infection, i.e. on average five years after vaccination. These long-term consequences highlight that imprinting certain functions (while deterring other responses) could offer benefits even for leaky vaccines. [ABSTRACT FROM AUTHOR]

Most HIV-1 infected individuals do not know their infection dates. Precise infection timing is crucial information for studies that document transmission networks or drug levels at infection. To improve infection timing, we used the prospective RV217 cohort where the window when plasma viremia becomes detectable is narrow: the last negative visit occurred a median of four days before the first detectable HIV-1 viremia with an RNA test, referred below as diagnosis. We sequenced 1,280 HIV-1 genomes from 39 participants at a median of 4, 32 and 170 days post-diagnosis. HIV-1 infections were dated by using sequence-based methods and a viral load regression method. Bayesian coalescent and viral load regression estimated that infections occurred a median of 6 days prior to diagnosis (IQR: 9–3 and 11–4 days prior, respectively). Poisson-Fitter, which analyzes the distribution of hamming distances among sequences, estimated a median of 7 days prior to diagnosis (IQR: 15–4 days) based on sequences sampled 4 days post-diagnosis, but it did not yield plausible results using sequences sampled at 32 days. Fourteen participants reported a high-risk exposure event at a median of 8 days prior to diagnosis (IQR: 12 to 6 days prior). These different methods concurred that HIV-1 infection occurred about a week before detectable viremia, corresponding to 20 days (IQR: 34–15 days) before peak viral load. Together, our methods comparison helps define a framework for future dating studies in early HIV-1 infection. Author summary: HIV-1 infected individuals rarely know when they became infected but knowing when an infection occurred provides critical information regarding HIV-1 pathogenesis and epidemiology. Using a unique cohort in which infection was known to have occurred in a narrow interval, we investigated methods to estimate the timing of infections. Several methods suggested that HIV-1 infection typically occurs a median of one week before the infection can be detected by HIV-1 RNA testing. Going forward, we provide a strategy that can be used to elucidate the origin of an acute/early infection. [ABSTRACT FROM AUTHOR]

The twelfth author's name is spelled incorrectly. Reference 1 Mdluli T, Jian N, Slike B, Paquin-Proulx D, Donofrio G, Alrubayyi A, et al. (2020) RV144 HIV-1 vaccination impacts post-infection antibody responses. [Extracted from the article]