Advances and gaps in SARS-CoV-2 infection models.

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

Histo-Blood Group Antigen Null Phenotypes Associated With a Decreased Risk of Clinical Rotavirus Vaccine Failure Among Children <2 Years of Age Participating in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in Kenya, Mali, and the Gambia.

BACKGROUND: Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children <2 years of age participating in the Vaccine Impact on Diarrhea in Africa Study in 3 sub-Saharan African countries. METHODS: Saliva was collected and tested for HBGA phenotype in children who received rotavirus vaccine. The association between secretor and Lewis phenotypes and rotavirus vaccine failure was examined overall and by infecting rotavirus genotype using conditional logistic regression in 218 rotavirus-positive cases with moderate-to-severe diarrhea and 297 matched healthy controls. RESULTS: Both nonsecretor and Lewis-negative phenotypes (null phenotypes) were associated with decreased rotavirus vaccine failure across all sites (matched odds ratio, 0.30 [95% confidence interval: 0.16-0.56] or 0.39 [0.25-0.62], respectively]. A similar decrease in risk against rotavirus vaccine failure among null HBGA phenotypes was observed for cases with P[8] and P[4] infection and their matched controls. While we found no statistically significant association between null HBGA phenotypes and vaccine failure among P[6] infections, the matched odds ratio point estimate for Lewis-negative individuals was >4. CONCLUSIONS: Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness.

Impact of Rotavirus Vaccine Introduction in Children Less Than 2 Years of Age Presenting for Medical Care With Diarrhea in Rural Matlab, Bangladesh.

BACKGROUND: Following the conclusion of a human rotavirus vaccine (HRV) cluster-randomized, controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age. METHODS: Interrupted time series were used to estimate the impact of HRV introduction. We used diarrheal surveillance collected between 2000 and 2014 within the 2 service delivery areas (International Centre for Diarrhoeal Disease Research, Bangladesh [icddr,b] service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System, administered by icddr,b. Age group-specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea diagnoses of any severity presenting to the hospital. We used 2 models to assess the impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period, using outcomes from control-only villages. RESULTS: Both models demonstrated a downward trend in RV+ diarrheal incidences in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impacts of HRV on RV+ diarrhea incidences in GSA villages were not observed in either model. Differences in population-level impacts between the 2 delivery areas may be due to the varied rotavirus vaccine coverage and presentation rates to the hospital. CONCLUSIONS: This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies are needed of the rotavirus vaccine impact after the nationwide introduction in Bangladesh.

Human papillomavirus genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia cases among HIV-infected men who have sex with men.

BACKGROUND: The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use. METHODS: HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines. RESULTS: HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%. CONCLUSIONS: Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men.

BACKGROUND: Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. METHODS: Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. RESULTS: Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. CONCLUSIONS: We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.

Standardized immunological assays for assessing COVID-19 vaccines by the CEPI-Centralized Laboratory Network.

The CEPI Centralized Laboratory Network implemented key steps in the transfer and monitoring of the developed immunological SARS-CoV-2 assays to ensure standardization across all the facilities of the network. This comprehensive evaluation reinforces the reliability of the generated data and establishes a solid foundation for a standardized approach, enabling precise inter-laboratory comparisons and contributing to the overall integrity of our network's clinical results. Herein, we will provide a brief elaboration on the specific measures and procedures implemented to standardize the transfer of assays across our network.

Standardised quantitative assays for anti-SARS-CoV-2 immune response used in vaccine clinical trials by the CEPI Centralized Laboratory Network: a qualification analysis.

BACKGROUND: Accurate quantitation of immune markers is crucial for ensuring reliable assessment of vaccine efficacy against infectious diseases. This study was designed to confirm standardised performance of SARS-CoV-2 assays used to evaluate COVID-19 vaccine candidates at the initial seven laboratories (in North America, Europe, and Asia) of the Coalition for Epidemic Preparedness Innovations (CEPI) Centralized Laboratory Network (CLN). METHODS: Three ELISAs (pre-spike protein, receptor binding domain, and nucleocapsid), a microneutralisation assay (MNA), a pseudotyped virus-based neutralisation assay (PNA), and an IFN-γ T-cell ELISpot assay were developed, validated or qualified, and transferred to participating laboratories. Immune responses were measured in ELISA laboratory units (ELU) for ELISA, 50% neuralisation dilution (ND50) for MNA, 50% neutralisation titre (NT50) for PNA, and spot-forming units for the ELISpot assay. Replicate assay results of well characterised panels and controls of blood samples from individuals with or without SARS-CoV-2 infection were evaluated by geometric mean ratios, standard deviation, linear regression, and Spearman correlation analysis for consistency, accuracy, and linearity of quantitative measurements across all laboratories. FINDINGS: High reproducibility of results across all laboratories was demonstrated, with interlaboratory precision of 4·1-7·7% coefficient of variation for all three ELISAs, 3·8-19·5% for PNA, and 17·1-24·1% for MNA, over a linear range of 11-30 760 ELU per mL for the three ELISAs, 14-7876 NT50 per mL for PNA, and 21-25 587 ND50 per mL for MNA. The MNA was also adapted for detection of neutralising antibodies against the major SARS-CoV-2 variants of concern. The results of PNA and MNA (r=0·864) and of ELISA and PNA (r=0·928) were highly correlated. The IFN-γ ELISpot interlaboratory variability was 15·9-49·9% coefficient of variation. Sensitivity and specificity were close to 100% for all assays. INTERPRETATION: The CEPI CLN provides accurate quantitation of anti-SARS-CoV-2 immune response across laboratories to allow direct comparisons of different vaccine formulations in different geographical areas. Lessons learned from this programme will serve as a model for faster responses to future pandemic threats and roll-out of effective vaccines. FUNDING: CEPI.

Clinical endpoints to inform vaccine policy: A systematic review of outcome measures from pediatric influenza vaccine efficacy trials.

INTRODUCTION: We conducted a systematic review of pediatric influenza vaccine efficacy trials to assess clinical outcome measures and whether the trials defined important public health endpoints. MATERIAL AND METHODS: We systematically identified phase 3 or 4 influenza vaccine randomized controlled trials among children ≤18 years of age with laboratory-confirmed influenza outcomes since 1980. We recorded countries, age groups, vaccine formulations, specimen collection criteria, laboratory diagnostics, primary and secondary outcome measures, and funders, and we determined income category for study countries. We used descriptive statistics to summarize study characteristics. We analyzed the studies overall and a subset of studies conducted in at least one low- and middle-income country (LMIC). RESULTS: From 6455 potentially relevant articles, we identified 41 eligible studies. Twenty-one studies (51%) were conducted in at least one LMIC, while the remaining studies (49%) were conducted in high-income countries only. Thirty-one studies (76%) included children younger than six years. We found 40 different primary outcome measures among the 41 eligible studies. Thirty-three studies (80%) reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. One study defined a primary outcome which captured more severe illness; however, cases were mostly due to high body temperature without other severity criteria. Of the 21 studies from at least one LMIC, 15 (71%) were published since 2010 and 17 (81%) enrolled children younger than six years. Eighteen (86%) studies from at least one LMIC reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. CONCLUSIONS: Among pediatric influenza vaccine efficacy trials, primary outcome measures and clinical specimen collection criteria were highly variable and, with one exception, focused on capturing any influenza illness. As most LMICs do not have influenza vaccination programs, our study highlights a potential data limitation affecting policy and implementation decisions in these settings.

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

BACKGROUND: The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. METHODS: This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. RESULTS: TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. CONCLUSIONS: This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings.

Do plant traits predict the competitive abilities of closely related species?

Invasive species are a threat to every ecosystem. There is a strong incentive to predict which species will become invasive before they become too widespread and unmanageable. Different approaches have been advocated to assess invasive species potential. These include examining plant functional traits, quantifying competitive ability and phylogenetic comparison. In this study, we conducted experiments based on the above approaches in a multi-year, temporally replicated, set of experiments to compare these assessment methods to determine the invasive potential of Japanese chaff flower (Achyranthes japonica). We compared plant traits and competitive ability of Japanese chaff flower with two agricultural invasive species, Palmer amaranth (Amaranthus palmeri) and tall waterhemp (Amaranthus tuberculatus), and one endangered plant species, bloodleaf (Iresine rhizomatosa), in the Amaranthaceae. Additionally, we assessed the invasive potential based on each of these approaches and determined the degree of agreement between them. A relatively conservative assessment integrating all three approaches would be that the competitive ability of closely related individuals with similar functional traits would share invasive potential. In a greenhouse experiment, each of the study species and soya beans were grown as monocultures and were evaluated to assess the drawdown of an aboveground (light) and a belowground (nitrogen) resource. In a field experiment, each study species was grown at varying densities per 15-cm-diameter pot with or without one or two soya bean plants, to simulate relative densities for soya beans grown in 38- and 76-cm-wide row spacing, respectively. In addition, Japanese chaff flower seedlings were planted either as un-manipulated seedlings or as a seedling cut back to the soil surface at the four-node stage (cut Japanese chaff flower) at which point seedlings have reached a perennial growth stage. The greenhouse experiment showed that each species drew down light differently, but not nitrogen. Shading decreased the aboveground biomass of the species in comparison with unshaded controls. Nitrogen, however, increased the aboveground biomass of Palmer amaranth and Japanese chaff flower. In the field experiment, a competitive effect ranking was determined to be: tall waterhemp ≥ Palmer amaranth = cut Japanese chaff flower ≥ uncut Japanese chaff flower ≥ bloodleaf, with the competitive response ranking being the inverse. These results suggest that under specific conditions, these closely related species do exhibit similar competitive abilities. Furthermore, the invasiveness and not the life history or habitat of these closely related species appeared to be the driving factor of competitiveness.

The dengue vaccine pipeline: Implications for the future of dengue control.

Dengue has become the most rapidly expanding mosquito-borne infectious disease on the planet, surpassing malaria and infecting at least 390 million people per year. There is no effective treatment for dengue illness other than supportive care, especially for severe cases. Symptoms can be mild or life-threatening as in dengue hemorrhagic fever and dengue shock syndrome. Vector control has been only partially successful in decreasing dengue transmission. The potential use of safe and effective tetravalent dengue vaccines is an attractive addition to prevent disease or minimize the possibility of epidemics. There are currently no licensed dengue vaccines. This review summarizes the current status of all dengue vaccine candidates in clinical evaluation. Currently five candidate vaccines are in human clinical trials. One has completed two Phase III trials, two are in Phase II trials, and three are in Phase I testing.

Trigonelline accumulation in leaves of Panicum virgatum seedlings.

Panicum virgatum is a dominant, native, perennial species found in the tallgrass prairie. In this study, we report the biosynthesis and accumulation of trigonelline (TRG) in leaves of P. virgatum in response to water-deficit stress. Once established, half of the seedlings underwent a drought stress treatment while the other half were watered daily (control). Relative water content (RWC) and trigonelline (TRG) concentrations were determined. RWC showed an interaction between moisture treatment and time, in which upland cultivars had the highest mean RWC compared with the lowland cultivars. The moisture treatments showed a significant difference in TRG concentration across all P. virgatum cultivars, which ranged from 0.5-31.8 microg/gFW(-1). There was a divergence in TRG accumulation between upland and lowland cultivars in relation to RWC. This study is the first to report TRG accumulation in the grass P. virgatum, and to test for differences in TRG with respect to water-deficit stress among cultivars. The effect of soil moisture levels on cultivars may be important in making an informed selection and the response of P. virgatum and other dominant grasses should be considered as a potential filter in tallgrass prairies for restoration. Physiological markers such as TRG and RWC can aid in this decision making process.

Alcohol consumption, one-carbon metabolites, liver cancer and liver disease mortality.

BACKGROUND: Excess alcohol consumption adversely affects one-carbon metabolism and increases the risk of liver disease and liver cancer. Conversely, higher folate levels have been inversely associated with liver damage. The current study investigated the effects of alcohol and one-carbon metabolite intake on liver cancer incidence and liver disease mortality within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. METHODS: Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs) in a population of 27,086 Finnish males with 194 incident liver cancers and 213 liver disease deaths. In a nested case-control subset (95 liver cancers, 103 controls), logistic regression was used to calculate odds ratios and 95% CIs for serum one-carbon metabolites in relation to liver cancer risk. RESULTS: Daily alcohol consumption of more than 20.44 g was associated with an increased risk of both liver cancer incidence (Hazard Ratio (HR) 1.52, 95%CI 1.06-2.18) and liver disease mortality (HR 6.68, 95%CI 4.16-10.71). These risks were unaffected by one-carbon metabolite intake. Similarly, in the case-control study, none of the serum one-carbon metabolites were associated with liver cancer. CONCLUSIONS: The current study provided no convincing evidence for a protective association of one-carbon metabolite intake or serum level on the risk of liver cancer or liver disease mortality.

Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality.

BACKGROUND: Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH-American Association of Retired Persons Diet and Health Study. METHODS: The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazards ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index, and diabetes. HCC incidence (n = 435) was determined through 2006 via linkage with cancer registries, and liver disease mortality (n = 789) was determined through 2008 via linkage to the U.S. Social Security Administration Death Master File and the National Death Index Plus by the National Center for Health Statistics. RESULTS: Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42-2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81-7.10), whereas folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction = 0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction = 0.54). CONCLUSIONS: These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC. IMPACT: Folate intake may be beneficial in the prevention of alcohol-associated HCC.

A comparison of human papillomavirus genotype-specific DNA and E6/E7 mRNA detection to identify anal precancer among HIV-infected men who have sex with men.

BACKGROUND: Human papillomavirus (HPV) RNA detection is reportedly more specific for the detection of anogenital precancer than HPV DNA but it is unknown whether this is due to detection of RNA or due to HPV genotype restriction. METHODS: A total of 363 human immunodeficiency virus (HIV)-positive men who have sex with men had two anal cytology samples taken and were evaluated using high-resolution anoscopy and biopsies of visible lesions. Anal specimens were tested for E6/E7 RNA for five carcinogenic HPV genotypes (HPV16, 18, 31, 33, and 45) and tested for the DNA of 13 carcinogenic HPV genotypes. RESULTS: DNA testing was more likely to be positive than RNA testing (53% vs. 48%; P = 0.02) for the same five HPV genotypes in aggregate. When restricted to five HPV genotypes targeted by the RNA test, the sensitivity to detect anal precancer was the same for DNA and RNA (81%), whereas RNA was more specific than DNA (65% vs. 58%; P = 0.007). In comparison, DNA detection of all 13 carcinogenic HPV genotypes was more sensitive (96% vs. 81%; P = 0.001) but much less specific (65% vs. 33%; P < 0.001) as compared with RNA detection of the five HPV genotypes. CONCLUSION: After controlling for HPV genotypes, RNA was only slightly more specific than DNA detection for anal precancer. IMPACT: DNA or RNA testing for a subset of the most carcinogenic HPV genotypes may be useful for distinguishing between those HPV-positive men at higher and lower risk of anal precancer and cancer.

Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated. METHODS: We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided. RESULTS: Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users. CONCLUSIONS: Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.