Explore the vast range of titles available.

Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly. Most COVID-19 vaccines require two doses but a single dose provides partial protection, so it is unclear how best to prioritize vaccine distribution in the context of limited supply. Here, the authors show that campaigns in which some age groups receive one dose while others receive both doses may be optimal.

Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VE DIS ). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection susceptibility ( VE SUSC ) or development of symptoms after infection (VE SYMP ). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VE SYMP and VE SUSC ) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VE SUSC and VE SYMP resulting in up to 100% VE DIS . We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VE DIS are projected to prevent 23–46% of infections and 31–46% of deaths over 1 year. In comparison, vaccines with 90% VE DIS are projected to prevent 37–64% of infections and 46–64% of deaths over 1 year. In both cases, there is a greater reduction if VE DIS is mediated mostly by VE SUSC . The use of a “symptom reducing” vaccine will require twice as many people vaccinated than a “susceptibility reducing” vaccine with the same 90% VE DIS to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.

Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or -positive, as well as KS-negative or -positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, brief episodic low viral load shedding, prolonged episodic medium viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection.

The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 μg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies.

A signature feature of HIV infection is poor control of herpes virus infections, which reactivate from latency and cause opportunistic infections. While the general mechanism underlying this observation is deficient CD4+T-cell function, it is unknown whether increased severity of herpes virus infections is due primarily to poor immune control in latent or lytic sites of infection, or whether CD4+ immunodeficiency leads to more critical downstream deficits in humoral or cell-mediated immunologic responses. Here we compare genital shedding patterns of herpes simplex virus-2 (HSV-2) in 98 HIV infected and 98 HIV uninfected men matched on length of infection, HSV-1 serostatus and nationality. We demonstrate that high copy HSV-2 shedding is more frequent in HIV positive men, particularly in participants with CD4+ T-cell count <200/μL. Genital shedding is more frequent due to higher rate of shedding episodes, as well as a higher proportion of prolonged shedding episodes. Peak episode viral load was not found to differ between HIV infected and uninfected participants regardless of CD4+ T-cell count. We simulate a mathematical model which recapitulates these findings and identifies that rate of HSV-2 release from neural tissue increases, duration of mucosal cytolytic immune protection decreases, and cell-free viral lifespan increases in HIV infected participants. These results suggest that increased HSV-2 shedding in HIV infected persons may be caused by impaired immune function in both latent and lytic tissue compartments, with deficits in clearance of HSV-2 infected cells and extracellular virus.

SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.

A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+) T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+) T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8(+) T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8(+) T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8(+) T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8(+) T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8(+) T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8(+) T cell responses to multiple conserved epitopes of HIV-1.

The rapid spread of highly transmissible SARS-CoV-2 variants combined with slowing pace of vaccination in Fall 2021 created uncertainty around the future trajectory of the epidemic in King County, Washington, USA. We analyzed the benefits of offering vaccination to children ages 5–11 and expanding the overall vaccination coverage using mathematical modeling. We adapted a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington, to simulate scenarios of vaccinating children aged 5–11 with different starting dates and different proportions of physical interactions (PPI) in schools being restored. Dynamic social distancing was implemented in response to changes in weekly hospitalizations. Reduction of hospitalizations and estimated time under additional social distancing measures are reported over the 2021–2022 school year. In the scenario with 85% vaccination coverage of 12+ year-olds, offering early vaccination to children aged 5–11 with 75% PPI was predicted to prevent 756 (median, IQR 301–1434) hospitalizations cutting youth hospitalizations in half compared to no vaccination and largely reducing the need for additional social distancing measures over the school year. If, in addition, 90% overall vaccination coverage was reached, 60% of remaining hospitalizations would be averted and the need for increased social distancing would almost certainly be avoided. Our work suggests that uninterrupted in-person schooling in King County was partly possible because reasonable precaution measures were taken at schools to reduce infectious contacts. Rapid vaccination of all school-aged children provides meaningful reduction of the COVID-19 health burden over this school year but only if implemented early. It remains critical to vaccinate as many people as possible to limit the morbidity and mortality associated with future epidemic waves.

The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CD8+ and CD4+ tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection; viral clearance always predominated within 24 hours of detection even when viral load exceeded 1 × 107 HSV DNA copies, and surges in granzyme B and IFN-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans. A sufficiently high density of HSV-2-specific Trm cells predicted rapid elimination of infected cells, but our data suggest that such Trm cell densities are relatively uncommon in infected tissues. At lower, more commonly observed Trm cell densities, Trm cells must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.

Modern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The optimal model of primary infection required no positive selection, suggesting that the host adaptive immune system reduces viral load but surprisingly does not drive observed viral evolution. Rather, the fitness (infectivity) of mutant variants is drawn from an exponential distribution in which most variants are slightly less infectious than their parents (nearly neutral evolution). This distribution was not largely different from either in vivo fitness distributions recorded beyond primary infection or in vitro distributions that are observed without adaptive immunity, suggesting the intrinsic viral fitness distribution may drive evolution. Simulated phylogenetic trees also agree with independent data and illuminate how phylogenetic inference must consider viral and immune-cell population dynamics to gain accurate mechanistic insights.