The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial.

BACKGROUND: Oral vaccines have lower efficacy in developing compared to developed countries. Poor water, sanitation, and hygiene (WASH) may contribute to reduced oral vaccine immunogenicity. METHODS: We conducted a cluster-randomized 2 × 2 factorial trial in rural Zimbabwe. Pregnant women and their infants were eligible if they lived in clusters randomized to (1) standard of care (52 clusters); (2) improved infant feeding (53 clusters); (3) WASH: ventilated improved pit latrine, 2 hand-washing stations, liquid soap, chlorine, infant play space, and hygiene counseling (53 clusters); or (4) feeding plus WASH (53 clusters). This substudy compared oral rotavirus vaccine (RVV) seroconversion (primary outcome), and seropositivity and geometric mean titer (GMT) (secondary outcomes), in WASH vs non-WASH infants by intention-to-treat analysis. RESULTS: We included 801 infants with documented RVV receipt and postvaccine titer measurements (329 from 84 WASH clusters; 472 from 102 non-WASH clusters); 328 infants with prevaccination titers were included in the primary outcome. Thirty-three of 109 (30.3%) infants in the WASH group seroconverted following rotavirus vaccination, compared to 43 of 219 (19.6%) in the non-WASH group (absolute difference, 10.6% [95% confidence interval {CI}, .54%-20.7%]; P = .031). In the WASH vs non-WASH groups, 90 of 329 (27.4%) vs 107 of 472 (22.7%) were seropositive postvaccination (absolute difference, 4.7% [95% CI, -1.4% to 10.8%]; P = .130), and antirotavirus GMT was 18.4 (95% CI, 15.6-21.7) U/mL vs 14.9 (95% CI, 13.2-16.8) U/mL (P = .072). CONCLUSIONS: Improvements in household WASH led to modest but significant increases in seroconversion to RVV in rural Zimbabwean infants. CLINICAL TRIALS REGISTRATION: NCT01824940.

A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4Δ30, Is Well Tolerated and Immunogenic in Flavivirus-Naive Older Adult Volunteers.

West Nile virus (WNV) is a major cause of mosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severe fatal neurologic infection. Adults aged >60 years are more susceptible to neuroinvasive disease accompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated West Nile virus vaccine, rWN/DEN4Δ30, was shown to be safe and immunogenic in healthy adults aged 18-50 years. This study evaluated rWN/DEN4Δ30 in flavivirus-naive adults aged 50-65 years and found it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safe and effective vaccine will be an important public health tool.

Influence of maternal and socioeconomic factors on breast milk fatty acid composition in urban, low-income families.

The lipid composition of breast milk may have a significant impact on early infant growth and cognitive development. Comprehensive breast milk data is lacking from low-income populations in the Indian subcontinent impeding assessment of deficiencies and limiting development of maternal nutritional interventions. A single breast milk specimen was collected within 6 weeks postpartum from two low-income maternal cohorts of exclusively breastfed infants, from Dhaka, Bangladesh (n = 683) and Kolkata, India (n = 372) and assayed for percentage composition of 26 fatty acids. Mature milk (>15 days) in Dhaka (n = 99) compared to Kolkata (n = 372) was higher in total saturated fatty acid (SFA; mean 48% vs. 44%) and disproportionately lower in ω3-polyunsaturated fatty acid (PUFA), hence the ω6- and ω3-PUFA ratio in Dhaka were almost double the value in Kolkata. In both sites, after adjusting for days of lactation, increased maternal education was associated with decreased SFA and PUFA, and increasing birth order or total pregnancies was associated with decreasing ω6-PUFA or ω3-PUFA by a factor of 0.95 for each birth and pregnancy. In Dhaka, household prosperity was associated with decreased SFA and PUFA and increased ω6- and ω3-PUFA. Maternal height was associated with increased SFA and PUFA in Kolkata (1% increase per 1 cm), but body mass index showed no independent association with either ratio in either cohort. In summary, the socioeconomic factors of maternal education and household prosperity were associated with breast milk composition, although prosperity may only be important in higher cost of living communities. Associated maternal biological factors were height and infant birth order, but not adiposity. Further study is needed to elucidate the underlying mechanisms of these effects.

A 12-Month-Interval Dosing Study in Adults Indicates That a Single Dose of the National Institute of Allergy and Infectious Diseases Tetravalent Dengue Vaccine Induces a Robust Neutralizing Antibody Response.

UNLABELLED: The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. CLINICAL TRIALS REGISTRATION: NCT01782300.

Delayed Dosing of Oral Rotavirus Vaccine Demonstrates Decreased Risk of Rotavirus Gastroenteritis Associated With Serum Zinc: A Randomized Controlled Trial.

BACKGROUND: Rotavirus is the world's leading cause of childhood diarrheal death. Despite successes, oral rotavirus vaccines are less effective in developing countries. In an urban slum of Dhaka, we performed active diarrhea surveillance to evaluate monovalent G1P[8] rotavirus vaccine (RV1) efficacy and understand variables contributing to risk of rotavirus diarrhea (RVD). METHODS: We performed a randomized controlled trial of monovalent oral rotavirus vaccine (RV1). Seven hundred healthy infants received RV1 or no RV1 (1:1) using delayed dosing (10 and 17 weeks) and were followed for 1 year. Intensive diarrhea surveillance was performed. The primary outcome was ≥1 episode of RVD. Nutritional, socioeconomic, and immunologic factors were assessed by logistic regression best-subsets analysis for association with risk of RVD and interactions with vaccine arm. RESULTS: Incidence of all RVD was 38.3 cases per 100 person-years. Per-protocol RV1 efficacy was 73.5% (95% confidence interval [CI], 45.8%-87.0%) against severe RVD and 51% (95% CI, 33.8%-63.7%) against all RVD. Serum zinc level (odds ratio [OR], 0.77; P = .002) and lack of rotavirus immunoglobulin A (IgA) seroconversion (OR, 1.95; P = .018) were associated with risk of RVD, independent of vaccination status. Water treatment and exclusive breastfeeding were of borderline significance. Factors not associated with RVD included height for age at 10 weeks, vitamin D, retinol binding protein, maternal education, household income, and sex. CONCLUSIONS: In an urban slum with high incidence of RVD, the efficacy of RV1 against severe RVD was higher than anticipated in the setting of delayed dosing. Lower serum zinc level and lack of IgA seroconversion were associated with increased risk of RVD independent of vaccination. CLINICAL TRIALS REGISTRATION: NCT01375647.

Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults.

BACKGROUND: The 4 serotypes of dengue virus, DENV-1-4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. METHODS: Two randomized, placebo-controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. RESULTS: A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. CONCLUSIONS: A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. CLINICAL TRIALS REGISTRATION: NCT01072786 and NCT01436422.

A single dose of any of four different live attenuated tetravalent dengue vaccines is safe and immunogenic in flavivirus-naive adults: a randomized, double-blind clinical trial.

BACKGROUND: Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection. METHODS: In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. RESULTS: A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%-90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. CONCLUSIONS: TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection.

Lack of homologous protection against Campylobacter jejuni CG8421 in a human challenge model.

BACKGROUND: Campylobacter jejuni is a common cause of diarrhea and is associated with serious postinfectious sequelae. Although symptomatic and asymptomatic infections are recognized, protective immunity is not well understood. Previous data suggests that interferon γ (IFN-γ) may be associated with protection. To better define the clinical and immunologic development of protective immunity to C. jejuni, we assessed the ability of an initial infection to prevent clinical illness after a second experimental infection. METHODS: Subjects with no clinical or immunologic evidence of prior infection with C. jejuni received an initial challenge with C. jejuni CG8421 with rechallenge 3 months later. The primary endpoint was campylobacteriosis, as defined by diarrhea and/or systemic signs. Close inpatient monitoring was performed. Serum immunoglobulin A (IgA) and immunoglobulin G (IgG), fecal IgA, IgA antibody-secreting cells (ASCs), and IFN-γ production were evaluated. All subjects were treated with antibiotics and were clinically well at discharge. RESULTS: Fifteen subjects underwent a primary infection with C. jejuni CG8421; 14 (93.3%) experienced campylobacteriosis. Eight subjects received the second challenge, and all experienced campylobacteriosis with similar severity. Immune responses after primary infection included serum IgA, IgG, ASC, and IFN-γ production. Responses were less robust after secondary infection. CONCLUSIONS: In naive healthy adults, a single infection with CG8421 did not protect against campylobacteriosis. Although protection has been demonstrated with other strains and after continuous environmental exposure, our work highlights the importance of prior immunity, repeated exposures, and strain differences in protective immunity to C. jejuni. CLINICAL TRIALS REGISTRATION: NCT01048112.

Determining the impact of vaccination on SARS-CoV-2 RT-PCR cycle threshold values and infectious viral titres.

Background: As the COVID-19 pandemic continues, efforts to better understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral shedding and transmission in both unvaccinated and vaccinated populations remain critical to informing public health policies and vaccine development. The utility of using real time RT-PCR cycle threshold values (CT values) as a proxy for infectious viral litres from individuals infected with SARS-CoV-2 is yet to be fully understood. This retrospective observational cohort study compares quantitative infectious viral litres derived from a focus-forming viral titre assay with SARS-CoV-2 RT-PCR CT values in both unvaccinated and vaccinated individuals infected with the Delta strain. Methods: Nasopharyngeal swabs positive for SARS-CoV-2 by RT-PCR with a CT value <27 collected from 26 June to 17 October 2021 at the University of Vermont Medical Center Clinical Laboratory for which vaccination records were available were included. Partially vaccinated and individuals <18 years of age were excluded. Infectious viral litres were determined using a micro-focus forming assay under BSL-3 containment. Results: In total, 119 specimens from 22 unvaccinated and 97 vaccinated individuals met all inclusion criteria and had sufficient residual volume to undergo viral titring. A negative correlation between RT-PCR CT values and viral litres was observed in both unvaccinated and vaccinated groups. No difference in mean CT value or viral titre was detected between vaccinated and unvaccinated groups. Viral litres did not change as a function of time since vaccination. Conclusions: Our results add to the growing body of knowledge regarding the correlation of SARS-CoV-2 RNA levels and levels of infectious virus. At similar CT values, vaccination does not appear to impact an individual's potential infectivity when infected with the Delta variant.

Associations between biomarkers of environmental enteric dysfunction and oral rotavirus vaccine immunogenicity in rural Zimbabwean infants.

BACKGROUND: Oral rotavirus vaccines (RVV) are poorly immunogenic in low-income countries. Environmental enteric dysfunction (EED) resulting from poor water, sanitation and hygiene (WASH) may contribute. We therefore tested associations between EED and RVV immunogenicity, and evaluated the effect of improved WASH on EED. METHODS: We measured nine biomarkers of EED among Zimbabwean infants born to mothers enrolled in a cluster-randomised 2 × 2 factorial trial of improved WASH and improved feeding between November 2012 and March 2015 (NCT01824940). We used multivariable regression to determine associations between EED biomarkers and RVV seroconversion, seropositivity and geometric mean titer. Log-binomial regression was used to evaluate the effect of improved WASH on EED. FINDINGS: Among 303 infants with EED biomarkers and immunogenicity data, plasma intestinal fatty-acid binding protein and stool myeloperoxidase were positively associated with RVV seroconversion; adjusted RR 1.63 (95%CI 1.04, 2.57) and 1.29 (95%CI 1.01, 1.65), respectively. There were no other associations between RVV immunogenicity and either individual biomarkers or EED domains (intestinal permeability, intestinal damage, intestinal inflammation and microbial translocation). EED biomarkers did not differ between randomised WASH and non-WASH groups. INTERPRETATION: We found no evidence that EED was associated with poor RVV immunogenicity. Contrary to our hypothesis, there was weak evidence that EED was associated with increased seroconversion. EED biomarkers were not affected by a package of household-level WASH interventions.