Characterization of immune responses to two and three doses of the adenoviral vectored vaccine ChAdOx1 nCov-19 and the whole virion inactivated vaccine BBV152 in a mix-and-match study in India.

Infections with SARS-CoV-2 variants and declining immunity after primary vaccination, encouraged the use of booster doses. Some countries changed their immunization programmes to boost with vaccines different from the ones in their original schedule, based on results from immunogenicity and effectiveness studies. This study reports immunological analysis of samples collected in a phase 4 randomized trial, where participants who had previously received two primary doses of ChAdOx1 nCov-19 (ChAd) or inactivated BBV152 vaccine were randomized to receive either ChAd or BBV152 booster and further categorized as: Group 1 (two primary doses of ChAd - ChAd booster), Group 2 (two primary doses of ChAd - BBV152 booster), Group 3 (two primary doses of BBV152 - ChAd booster), and Group 4 (two primary doses of BBV152 - BBV152 booster). SARS-CoV-2 specific cellular and humoral responses at day 0 (pre-boost samples 12-36 weeks after the second primary dose), and at day 28 post booster, were measured in a subset of participants (ChAd recipients, n = 37 and BBV152 recipients, n = 36). Additionally, on day180 post-booster humoral responses were assessed for the entire cohort (N = 378). Primary vaccination with 2 doses of BBV152 generated higher memory-B cells (median% 0.41 vs 0.35) and cytokine producing CD8-Tcells (median% 0.09 vs 0.04) while lower anti-spike IgG levels (medianAU/ml: 12,433 vs 27,074) as compared to ChAd. Irrespective of the primary vaccine received, ChAd boosted individuals generated higher memory-B cell frequencies and anti-spike IgG levels as compared to BBV152 booster. The percentage ACE-2 inhibition against Omicron and its sub-variants was higher in Group 3 (median > 60 %) as compared to other groups (median < 25 %). At day180 post booster the hierarchy of the antibody amounts was Group 1 âˆ¼ Group 2 âˆ¼ Group 3 > Group 4. Sustained humoral and robust cellular immune response to SARS-CoV-2 can be obtained with ChAd booster irrespective of the primary vaccination regimen. The trial is registered with ISRTCN (CTRI/2021/08/035648).

Burden of Typhoid and Paratyphoid Fever in India.

BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

Immunogenicity and safety of homologous and heterologous booster vaccination of ChAdOx1 nCoV-19 (COVISHIELD™) and BBV152 (COVAXIN®): a non-inferiority phase 4, participant and observer-blinded, randomised study.

Background: Primary SARS-CoV-2 vaccination has been shown to wane with time and provide lower protection from disease with new viral variants, prompting the WHO to recommend the administration of booster doses. We determined the safety and immunogenicity of homologous or heterologous boosters with ChAdOx1 nCoV-19 (COVISHIELD™) or BBV152 (COVAXIN®), the two vaccines used widely for primary immunization in India, in participants who had already received two primary doses of these vaccines. Methods: Participants primed with two doses each of COVISHIELD™ or COVAXIN® 12-36 weeks previously, were randomised to receive either COVISHIELD™ or COVAXIN® booster in a 1:1 ratio. The primary outcome was day 28 post-booster anti-spike IgG seropositivity and secondary outcomes were anti-spike IgG levels and assessment of safety and reactogenicity. The results of 90 days intention-to-treat analysis are presented. This trial is registered with ISRCTN (CTRI/2021/08/035648). Findings: In the COVISHIELD™ primed group with 200 participants, the seropositivity 28 days post booster in the heterologous COVAXIN® arm was 99% and non-inferior to the homologous COVISHIELD™ arm, which was also 99% (difference 0%; 95% CI: -2.8% to 2.7%). The geometric mean concentration (GMC) of anti-spike antibodies following heterologous COVAXIN® boost on day 28 was 36,190.78 AU/mL (95% CI: 30,526.64-42,905.88) while the GMC following homologous COVISHIELD™ boost was 97,445.09 AU/mL (82,626.97-114,920.7). In the COVAXIN® primed group with 204 participants, the seropositivity 28 days post booster in the heterologous COVISHIELD™ arm was 100% and non inferior to the homologous COVAXIN® arm which was 96% (difference 4%, 95% CI: 0.2%-7.8%). The GMC following heterologous COVISHIELD™ boost was 241,681.6 AU/mL (95% CI: 201,380.2-290,048.3) compared to homologous COVAXIN® boost, which was 48,473.94 AU/mL (95% CI: 38,529.56-60,984.95). The day 28 geometric mean ratio (GMR) of the anti-spike IgG between the heterologous and homologous boosted arms was 0.42 (95% CI: 0.34-0.52) in the COVISHIELD™ primed group and 5.11 (95% CI: 3.83-6.81) in the COVAXIN® primed group. There were no related serious adverse events reported in any group. Interpretation: Homologous and heterologous boosting with COVISHIELD™ or COVAXIN® in COVISHIELD™ or COVAXIN® primed individuals are immunogenic and safe. A heterologous boost with COVISHIELD™ after COVAXIN® prime offers the best immune response among the four combinations evaluated. Funding: Azim Premji Foundation and Bill and Melinda Gates Foundation.

Novel prosthodontic technique in fabrication of customized nasal stent in an infant.

Burn injuries have a major impact on the physical and functional aspects of patients, thereby affecting their quality of life. Nasal stenosis which occurs as a result of wound contraction may lead to serious complications if not intervened at the earliest. In the prosthodontic front, nasal stents may be utilized in conjunction with reconstructive surgery procedures to minimize scar contraction and prevent nasal stenosis. This clinical report focuses on a customized technique in the fabrication of nasal stent to maintain the nasal airway patency in an infant who had suffered burn injuries. An intraoral tip was employed as a receptacle for accurate impression making, followed by the insertion of an intermediate stent fashioned from a scalp vein set catheter. The definitive stent fabricated using methyl methacrylate resin served to maintain the patency of the nasal passageway.

Sero-Surveillance to Monitor the Trend of SARS-CoV-2 Infection Transmission in India: Study Protocol for a Multi Site, Community Based Longitudinal Cohort Study.

Introduction: Large-scale sero-prevalence studies with representation from all age groups are required to estimate the true burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the community. Serial serological surveys in fixed cohorts enable study of dynamics of viral transmission and correlates of immune response over time in the context of gradual introduction of COVID-19 vaccines and repeated upsurge of cases during the pandemic. Methods: This longitudinal study will involve follow-up of a cohort of 25,000 individuals (5,000 per site) aged 2 years and above recruited from five existing demographic surveillance sites in India. The cohort will be tested for the presence of IgG antibodies against S1/S2 spike protein subunits of SARS-CoV-2 in four rounds; once at baseline and subsequently, at intervals of 4 months for a year between January 2021 and January 2022. Neutralization assays will be carried out in a subset of seropositive samples in each round to quantify the antibody response and to estimate the durability of antibody response. Serial serological surveys will be complemented by fortnightly phone based syndromic surveillance to assess the burden of symptomatic acute febrile illness/ influenza like illness in the same cohort. A bio-repository will also be established to store the serum samples collected in all rounds of serological surveys. Discussion: The population based sero-epidemiological studies will help to determine the burden of COVID-19 at the community level in urban and rural Indian populations and guide in monitoring the trends in the transmission of SARS-CoV-2 infection. Risk factors for infection will be identified to inform future control strategies. The serial serological surveys in the same set of participants will help determine the viral transmission dynamics and durability of neutralizing immune response in participants with or without symptomatic COVID infection.

Therapeutic role of corticosteroids in COVID-19: a systematic review of registered clinical trials.

BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 as a global pandemic. Though antiviral drugs and antimalarial drugs are considered treatment options for treating coronavirus disease 2019 (COVID-19), no specific antivirals are currently available for its treatment. Efficient use of drug discovery approaches including repurposing or repositioning of drugs used in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) is considered recently. The widespread application of corticosteroid therapy in COVID-19 should be backed with careful documented pragmatic research of its use in this context. MAIN BODY: This article aims to analyze various trials registered across the globe providing an overall picture of the use of corticosteroids in the treatment of COVID-19. An extensive search was conducted on the clinical trial registries around the world to identify all the trials reporting information regarding the use of corticosteroids in COVID-19. Our initial search returned 231 trials, out of which 60 trials were finally included in the analysis. Fifty-six studies were interventional trials, and all the trials had clearly defined primary and secondary outcomes of interest, of which only 11 trials had evaluation of respiratory rate as one of their outcomes. CONCLUSION: Few preliminary trial findings show promising results and recommend the use of methylprednisolone and dexamethasone in the severe form of the disease; however, there is insufficient data to prove its benefits over its risks. Routine use of corticosteroids should be favored only after a better insight is obtained, with the completion of these trials.

Healthcare Utilization Survey in the Hybrid Model of the Surveillance for Enteric Fever in India (SEFI) Study: Processes, Monitoring, Results, and Challenges.

BACKGROUND: Lack of reliable data in India drove the "Surveillance of Enteric Fever in India" (SEFI) concept. Hybrid surveillance, combining facility-based surveillance for the crude incidence, and a community-based healthcare utilization survey (HCUS) to calculate the factor needed to arrive at the adjusted incidence, was used in 6 sites. The HCUS aimed to determine the percentage of utilization of study facilities by the catchment population for hospitalizations due to febrile illness. METHODS: Population proportional to size sampling and systematic random sampling, in 2 stages, were used to survey 5000 households per site. Healthcare utilization was assessed. RESULTS: Febrile illness accounted for 20% of admissions among 137 990 individuals from 30 308 households. Only 9.6%-38.3% of those admitted with febrile illness sought care in the study hospitals. The rate of rural utilization of the private sector for hospitalization was 67.6%. The rate of hospitalization for febrile illness, per 1000 population, ranged from 2.6 in Manali to 9.6 in Anantapur; for 25.8% of the deaths associated with febrile illness, no facility was used before death. CONCLUSIONS: One in 5 hospitalizations were associated with fever. Rural utilization of the private sector for hospitalization due to febrile illness was more than that of the public sector. Healthcare utilization patterns for hospital admissions due to febrile illness varied across sites. A meticulously performed HCUS is pivotal for accurate incidence estimation in a hybrid surveillance. CLINICAL TRIALS REGISTRATION: ISRCTN72938224.

Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India.

BACKGROUND: The case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs. METHODS: We aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017-2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital. RESULTS: A total of 1236 hospitalized patients with blood culture-confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%-1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%-.29%) for all enteric fevers. CONCLUSIONS: Our estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

Geographic Pattern of Typhoid Fever in India: A Model-Based Estimate of Cohort and Surveillance Data.

BACKGROUND: Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India. METHODS: We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence. RESULTS: We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north. CONCLUSIONS: There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.

Cost of Illness Due to Severe Enteric Fever in India.

BACKGROUND: Lack of robust data on economic burden due to enteric fever in India has made decision making on typhoid vaccination a challenge. Surveillance for Enteric Fever network was established to address gaps in typhoid disease and economic burden. METHODS: Patients hospitalized with blood culture-confirmed enteric fever and nontraumatic ileal perforation were identified at 14 hospitals. These sites represent urban referral hospitals (tier 3) and smaller hospitals in urban slums, remote rural, and tribal settings (tier 2). Cost of illness and productivity loss data from onset to 28 days after discharge from hospital were collected using a structured questionnaire. The direct and indirect costs of an illness episode were analyzed by type of setting. RESULTS: In total, 274 patients from tier 2 surveillance, 891 patients from tier 3 surveillance, and 110 ileal perforation patients provided the cost of illness data. The mean direct cost of severe enteric fever was US$119.1 (95% confidence interval [CI], US$85.8-152.4) in tier 2 and US$405.7 (95% CI, 366.9-444.4) in tier 3; 16.9% of patients in tier 3 experienced catastrophic expenditure. CONCLUSIONS: The cost of treating enteric fever is considerable and likely to increase with emerging antimicrobial resistance. Equitable preventive strategies are urgently needed.