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.
Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with ...Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.
We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28.
A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval CI, 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.
Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).
HIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 ...and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old.
For this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics.
We identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2·7, 95% CI 2·2–3·4; number of estimates Ne=22) and was roughly doubled among higher-risk populations (1·7, 1·4–2·1; Ne=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4·7, 2·2–10·1; Ne=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident).
We found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection.
World Health Organization.
SARS-CoV-2 is difficult to contain because many transmissions occur during pre-symptomatic infection. Unlike influenza, most SARS-CoV-2-infected people do not transmit while a small percentage infect ...large numbers of people. We designed mathematical models which link observed viral loads with epidemiologic features of each virus, including distribution of transmissions attributed to each infected person and duration between symptom onset in the transmitter and secondarily infected person. We identify that people infected with SARS-CoV-2 or influenza can be highly contagious for less than 1 day, congruent with peak viral load. SARS-CoV-2 super-spreader events occur when an infected person is shedding at a very high viral load and has a high number of exposed contacts. The higher predisposition of SARS-CoV-2 toward super-spreading events cannot be attributed to additional weeks of shedding relative to influenza. Rather, a person infected with SARS-CoV-2 exposes more people within equivalent physical contact networks, likely due to aerosolization.
To affect the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project ...multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies, or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop may decrease shedding duration and immune response intensity but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed before viral peak during presymptomatic infection could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration, not AUC, is most predictive of clinical severity.
Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed ...to cover HIV's extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10-1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.
Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been ...attributed to viral replication in an ART sanctuary and long-lived and/or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a fossil record of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.
Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to ...many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy.
Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VE
). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection ...susceptibility (VE
) or development of symptoms after infection (VE
). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VE
and VE
) 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
and VE
resulting in up to 100% VE
. 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
are projected to prevent 23-46% of infections and 31-46% of deaths over 1 year. In comparison, vaccines with 90% VE
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
is mediated mostly by VE
. The use of a "symptom reducing" vaccine will require twice as many people vaccinated than a "susceptibility reducing" vaccine with the same 90% VE
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.
A reservoir of HIV-infected cells that persists despite suppressive antiretroviral therapy (ART) is the source of viral rebound upon ART cessation and the major barrier to a cure. Understanding ...reservoir seeding dynamics will help identify the best timing for HIV cure strategies. Here we characterize reservoir seeding using longitudinal samples from before and after ART initiation in individuals who sequentially became infected with genetically distinct HIV variants (superinfected). We previously identified cases of superinfection in a cohort of Kenyan women, and the dates of both initial infection and superinfection were determined. Six women, superinfected 0.2-5.2 years after initial infection, were subsequently treated with ART 5.4-18.0 years after initial infection. We performed next-generation sequencing of HIV gag and env RNA from plasma collected during acute infection as well as every ~2 years thereafter until ART initiation, and of HIV DNA from PBMCs collected 0.9-4.8 years after viral suppression on ART. We assessed phylogenetic relationships between HIV DNA reservoir sequences and longitudinal plasma RNA sequences prior to ART, to determine proportions of initial and superinfecting variants in the reservoir. The proportions of initial and superinfection lineage variants present in the HIV DNA reservoir were most similar to the proportions present in HIV RNA immediately prior to ART initiation. Phylogenetic analysis confirmed that the majority of HIV DNA reservoir sequences had the smallest pairwise distance to RNA sequences from timepoints closest to ART initiation. Our data suggest that while reservoir cells are created throughout pre-ART infection, the majority of HIV-infected cells that persist during ART entered the reservoir near the time of ART initiation. We estimate the half-life of pre-ART DNA reservoir sequences to be ~25 months, which is shorter than estimated reservoir decay rates during suppressive ART, implying continual decay and reseeding of the reservoir up to the point of ART initiation.
PDF
