Julian Wolfson

Immunogenicity of a Meningococcal B Vaccine during a University Outbreak

BACKROUND In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearsons correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearsons correlation,-0.06; P=0.43). CONCLUSIONS Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).

Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia

BACKGROUND The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. METHODS We initiated a randomized, placebo‐controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3‐EBO‐Z) and the recombinant vesicular stomatitis virus vaccine (rVSV&Dgr;G‐ZEBOV‐GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated. RESULTS A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection‐site reactions (in 28.5% of the patients in the ChAd3‐EBO‐Z group and 30.9% of those in the rVSV&Dgr;G‐ZEBOV‐GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3‐EBO‐Z group, in 47 (9.4%) in the rVSV&Dgr;G‐ZEBOV‐GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3‐EBO‐Z group and in 83.7% of those in the rVSV&Dgr;G‐ZEBOV‐GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3‐EBO‐Z group (63.5%) and in those in the rVSV&Dgr;G‐ZEBOV‐GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons). CONCLUSIONS A randomized, placebo‐controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407.)

Adjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy

Background Non-AIDS conditions such as cardiovascular disease and non-AIDS defining cancers dominate causes of morbidity and mortality among persons with HIV on suppressive combination antiretroviral therapy. Accurate estimates of disease incidence and of risk factors for these conditions are important in planning preventative efforts. Methods With use of medical records, serious non-AIDS events, AIDS events, and causes of death were adjudicated using pre-specified criteria by an Endpoint Review Committee in two large international trials. Rates of serious non-AIDS which include cardiovascular disease, end-stage renal disease, decompensated liver disease, and non-AIDS cancer, and other serious (grade 4) adverse events were determined, overall and by age, over a median follow-up of 4.3 years for 3,570 participants with CD4+ cell count ≥300 cells/mm3 who were taking antiretroviral therapy and had an HIV RNA level ≤500 copies/mL. Cox models were used to examine the effect of age and other baseline factors on risk of a composite outcome of all-cause mortality, AIDS, or serious non-AIDS. Results Five-year Kaplan-Meier estimates of the composite outcome, overall and by age were 8.3% (overall), 3.6% (<40), 8.7% (40–49) and 16.1% (≥50), respectively (p<0.001). In addition to age, smoking and higher levels of interleukin-6 and D-dimer were significant predictors of the composite outcome. The composite outcome was dominated by serious non-AIDS events (overall 65% of 277 participants with a composite event). Most serious non-AIDS events were due to cardiovascular disease and non-AIDS cancers. Conclusions To date, few large studies have carefully collected data on serious non-AIDS outcomes. Thus, reliable estimates of event rates are scarce. Data cited here, from a geographically diverse cohort, will be useful for planning studies of interventions aimed at reducing rates of serious non-AIDS events among people with HIV.

Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy.

Background Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts. Methods In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer. Results Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal. Conclusions Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.

Portion size effects on weight gain in a free living setting

Examine the effect of weekday exposure over 6 months to different lunch sizes on energy intake and body weight in a free‐living sample of working adults.

Statistical Identifiability and the Surrogate Endpoint Problem, with Application to Vaccine Trials

Given a randomized treatment Z, a clinical outcome Y, and a biomarker S measured some fixed time after Z is administered, we may be interested in addressing the surrogate endpoint problem by evaluating whether S can be used to reliably predict the effect of Z on Y. Several recent proposals for the statistical evaluation of surrogate value have been based on the framework of principal stratification. In this article, we consider two principal stratification estimands: joint risks and marginal risks. Joint risks measure causal associations (CAs) of treatment effects on S and Y, providing insight into the surrogate value of the biomarker, but are not statistically identifiable from vaccine trial data. Although marginal risks do not measure CAs of treatment effects, they nevertheless provide guidance for future research, and we describe a data collection scheme and assumptions under which the marginal risks are statistically identifiable. We show how different sets of assumptions affect the identifiability of these estimands; in particular, we depart from previous work by considering the consequences of relaxing the assumption of no individual treatment effects on Y before S is measured. Based on algebraic relationships between joint and marginal risks, we propose a sensitivity analysis approach for assessment of surrogate value, and show that in many cases the surrogate value of a biomarker may be hard to establish, even when the sample size is large.

MRKAd5 HIV-1 Gag/Pol/Nef Vaccine-Induced T-Cell Responses Inadequately Predict Distance of Breakthrough HIV-1 Sequences to the Vaccine or Viral Load

Background The sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect. Methods Ninety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits. Findings Vaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30). Interpretation Despite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.

Snacking Behaviors, Diet Quality, and Body Mass Index in a Community Sample of Working Adults

BACKGROUND Snacking behaviors have been linked with higher energy intake and excess weight. However, results have been inconsistent. In addition, few data are available on the extent to which snacking affects diet quality. OBJECTIVE This study describes snacking behaviors, including total snacking energy, frequency, time of day, and percentage of snacking energy intake by food groups, and their associations with diet quality and body mass index (BMI; calculated as kg/m(2)). DESIGN Snacking behaviors and dietary intake were examined cross-sectionally among 233 adults participating in a community-based worksite nutrition intervention from September 2010 through February 2013. Three telephone-administered 24-hour dietary recalls were collected (2 weekdays; 1 weekend day). Diet quality was characterized by the Healthy Eating Index 2010 and BMI was computed using measured height and weight. SETTING The setting was a large metropolitan medical complex in Minneapolis, Minnesota. MAIN OUTCOME MEASURES Outcome measures included diet quality and BMI. STATISTICAL ANALYSES General linear regression models were used to examine associations between each of the snacking behaviors as independent variables, and diet quality and BMI as dependent variables. RESULTS Percent of snacking energy from fruit and juice (β=.13; P=0.001) and nuts (β=.16; P=0.008) were significantly positively associated with diet quality. Percent of snacking energy from desserts and sweets (β=-.16; P<0.001) and sugar-sweetened beverages (β=-.22; P=0.024) were significantly inversely associated. Percent of snacking energy from vegetables (β=-.18; P=0.044) was significantly associated with lower BMI. Percent snacking energy from desserts and sweets was significantly associated with a higher BMI (β=.04; P=0.017). CONCLUSIONS Snack food choices, but not total energy from snacks, frequency, or time of day, were significantly associated with diet quality and BMI.

Design and Estimation for Evaluating Principal Surrogate Markers in Vaccine Trials

In vaccine research, immune biomarkers that can reliably predict a vaccines effect on the clinical endpoint (i.e., surrogate markers) are important tools for guiding vaccine development. This article addresses issues on optimizing two-phase sampling study design for evaluating surrogate markers in a principal surrogate framework, motivated by the design of a future HIV vaccine trial. To address the problem of missing potential outcomes in a standard trial design, novel trial designs have been proposed that utilize baseline predictors of the immune response biomarker(s) and/or augment the trial by vaccinating uninfected placebo recipients at the end of the trial and measuring their immune biomarkers. However, inefficient use of the augmented information can lead to counter-intuitive results on the precision of estimation. To remedy this problem, we propose a pseudo-score type estimator suitable for the augmented design and characterize its asymptotic properties. This estimator has superior performance compared with existing estimators and allows calculation of analytical variances useful for guiding study design. Based on the new estimator we investigate in detail the problem of optimizing the sampling scheme of a biomarker in a vaccine efficacy trial for efficiently estimating its surrogate effect, as characterized by the vaccine efficacy curve (a causal effect predictiveness curve) and by the predicted overall vaccine efficacy using the biomarker.

Prevalence of anemia in pregnant women and its effect on neonatal outcomes in Northeast India

Abstract Objectives: To determine the prevalence of anemia in pregnant women and characterize its effect on neonatal outcome in Northeast India. Patients and methods: Four hundred and seventy mothers and their newborn infants during a one month period were included. The association between maternal hemoglobin (Hb) at delivery and neonatal outcomes were determined. Results: Anemia (Hb < 110 g/L) was present in 421 (89.6%) mothers with 35 (8.3%) having severe anemia(Hb < 70 g/L). After adjusting for maternal and neonatal variables, each 10 g/L decrease in maternal Hb was associated with 0.18 week decrease in gestational length (p = 0.003) and 21 g decrease in birth weight (p = 0.093). Severe maternal anemia was associated with 0.63week (95% CI, 0.03–1.23week) shorter gestation, 481 g (95% CI, 305–658 g) lower birth weight and 89% increased risk of small-for-gestation (OR 1.89, 95% CI, 1.25–2.86)in the offspring, compared with those born to mothers without anemia (p < 0.001). Conclusion: Maternal anemia was highly prevalentin this population. Lower gestational age and birth weight, and increased risk of small-for-gestation were associated with maternal anemia, especially when maternal Hb was <80 g/L. Maternal anemia needs urgent attention to improve neonatal outcome in this population.