Intussusception after Rotavirus Vaccine Introduction in India.

BACKGROUND: A three-dose, oral rotavirus vaccine (Rotavac) was introduced in the universal immunization program in India in 2016. A prelicensure trial involving 6799 infants was not large enough to detect a small increased risk of intussusception. Postmarketing surveillance data would be useful in assessing whether the risk of intussusception would be similar to the risk seen with different rotavirus vaccines used in other countries. METHODS: We conducted a multicenter, hospital-based, active surveillance study at 27 hospitals in India. Infants meeting the Brighton level 1 criteria of radiologic or surgical confirmation of intussusception were enrolled, and rotavirus vaccination was ascertained by means of vaccination records. The relative incidence (incidence during the risk window vs. all other times) of intussusception among infants 28 to 365 days of age within risk windows of 1 to 7 days, 8 to 21 days, and 1 to 21 days after vaccination was evaluated by means of a self-controlled case-series analysis. For a subgroup of patients, a matched case-control analysis was performed, with matching for age, sex, and location. RESULTS: From April 2016 through June 2019, a total of 970 infants with intussusception were enrolled, and 589 infants who were 28 to 365 days of age were included in the self-controlled case-series analysis. The relative incidence of intussusception after the first dose was 0.83 (95% confidence interval [CI], 0.00 to 3.00) in the 1-to-7-day risk window and 0.35 (95% CI, 0.00 to 1.09) in the 8-to-21-day risk window. Similar results were observed after the second dose (relative incidence, 0.86 [95% CI, 0.20 to 2.15] and 1.23 [95% CI, 0.60 to 2.10] in the respective risk windows) and after the third dose (relative incidence, 1.65 [95% CI, 0.82 to 2.64] and 1.08 [95% CI, 0.69 to 1.73], respectively). No increase in intussusception risk was found in the case-control analysis. CONCLUSIONS: The rotavirus vaccine produced in India that we evaluated was not associated with intussusception in Indian infants. (Funded by the Bill and Melinda Gates Foundation and others.).

Metabolic syndrome in people living with antiretroviral therapy: A cross-sectional investigation from Pune, India.

Background: Improved longevity of people living with HIV on highly active antiretroviral therapy and accelerated aging processes are considered contributory to Metabolic Syndrome. Objectives: The current study investigated metabolic syndrome (MetS) in people living with HIV (PLH) who were receiving antiretroviral therapy (ART) under the ongoing National AIDS Control Program. Methods: Clinic attendees (n = 3088) who were on ART for more than 6 months constituted the sampling frame, from which 378 study participants were randomly drawn and included in the analysis following the eligibility check. One hundred and fifty-nine clinic attendees, initiated on ART in ≤6 months, provided an opportunity to estimate the prevalence of MetS in them. Sixty-two PLH from this smaller group were enrolled. Results: MetS was found among 19% (73/378; 95% confidence interval [CI] 15.5%-23.7%) PLH who were on ART >6 months compared with 24% (15/62; 95% CI 14.2%-36.7%) in those who were on ART for ≤6 months based on harmonization criteria for the Asian population; the confidence intervals overlapped and apparently observed difference was not statistically significant. Adjusted for age, body mass index (BMI), protease inhibitor (PI)-based ART regimen, duration of ART, insulin resistance (IR), reported family history of hypertension and residential setting, factors independently associated with MetS were PI containing ART regimen, IR, duration of ART intake and BMI. In the adjusted model, the odds of MetS were three times higher among PLH on PI containing ART regimen (95% CI of adjusted odds ratio; aOR 1.27-8.51) and those having IR (95% CI of aOR 1.48-5.07). The odds of MetS among PLH with BMI ≥23 kg/m2 was 4 (95% CI of aOR 2.08-6.81) times higher than those with lower BMI. Conclusions: MetS in PLH requires the attention of health-care workers in India. Appropriate screening would help initiate early management.

Investigations of seasonal outbreaks of acute encephalitis syndrome due to Orientia tsutsugamushi in Gorakhpur region, India: A One Health case study.

Gorakhpur division consisting of Gorakhpur and neighboring districts Deoria, Kushinagar and Maharajganj in Uttar Pradesh, India, have been witnessing seasonal outbreaks of acute encephalitis syndrome (AES) among children for the last three decades. Investigations conducted during 2005 identified Japanese encephalitis (JE) virus as an aetiology of AES. With the introduction of JE vaccination and other control strategies, the incidence of JE in the region declined, however, outbreaks of acute febrile illness with neurological manifestations continued to occur. Subsequent investigations identified Orientia tsutsugamushi, as the major aetiology of AES outbreaks in the region. This review details clinical, epidemiological, animal and entomological investigations conducted for AES due to O. tsutsugamushi during 2015 and 2017 in Gorakhpur region. Surveillance of acute febrile illness among children attending peripheral health facilities identified scrub typhus as an important aetiology of febrile illness during monsoon and post-monsoon months. Population-based serosurveys indicated high endemicity of scrub typhus. Entomological studies demonstrated natural infection of O. tsutsugamushi in small animal hosts and vector mites. Children acquired this infection through recent exposure to outdoor environment, while playing, or visiting fields or defecating in open fields. A few of the children with scrub typhus progress to develop CNS manifestations. Hence, early administration of appropriate antibiotics is crucial in preventing progression of AFI due to scrub typhus to AES. The investigations conducted by the multi-disciplinary team helped understand the transmission dynamics of scrub typhus in Gorakhpur division and recommend strategies for its control.

Diversity of rotavirus genotypes circulating in children < 5 years of age hospitalized for acute gastroenteritis in India from 2005 to 2016: analysis of temporal and regional genotype variation.

BACKGROUND: From 2016, the Government of India introduced the oral rotavirus vaccine into the national immunization schedule. Currently, two indigenously developed vaccines (ROTAVAC, Bharat Biotech; ROTASIIL, Serum Institute of India) are included in the Indian immunization program. We report the rotavirus disease burden and the diversity of rotavirus genotypes from 2005 to 2016 in a multi-centric surveillance study before the introduction of vaccines. METHODS: A total of 29,561 stool samples collected from 2005 to 2016 (7 sites during 2005-2009, 3 sites from 2009 to 2012, and 28 sites during 2012-2016) were included in the analysis. Stools were tested for rotavirus antigen using enzyme immunoassay (EIA). Genotyping was performed on 65.8% of the EIA positive samples using reverse transcription- polymerase chain reaction (RT-PCR) to identify the G (VP7) and P (VP4) types. Multinomial logistic regression was used to quantify the odds of detecting genotypes across the surveillance period and in particular age groups. RESULTS: Of the 29,561 samples tested, 10,959 (37.1%) were positive for rotavirus. There was a peak in rotavirus positivity during December to February across all sites. Of the 7215 genotyped samples, G1P[8] (38.7%) was the most common, followed by G2P[4] (12.3%), G9P[4] (5.8%), G12P[6] (4.2%), G9P[8] (4%), and G12P[8] (2.4%). Globally, G9P[4] and G12P[6] are less common genotypes, although these genotypes have been reported from India and few other countries. There was a variation in the geographic and temporal distribution of genotypes, and the emergence or re-emergence of new genotypes such as G3P[8] was seen. Over the surveillance period, there was a decline in the proportion of G2P[4], and an increase in the proportion of G9P[4]. A higher proportion of mixed and partially typed/untyped samples was also seen more in the age group 0-11 months. CONCLUSIONS: This 11 years surveillance highlights the high burden of severe rotavirus gastroenteritis in Indian children < 5 years of age before inclusion of rotavirus vaccines in the national programme. Regional variations in rotavirus epidemiology were seen, including the emergence of G3P[8] in the latter part of the surveillance. Having pre-introduction data is important to track changing epidemiology of rotaviruses, particularly following vaccine introduction.

Seroprevalence & seroincidence of Orientia tsutsugamushi infection in Gorakhpur, Uttar Pradesh, India: A community-based serosurvey during lean (April-May) & epidemic (October-November) periods for acute encephalitis syndrome.

Background & objectives: In India, acute encephalitis syndrome (AES) cases are frequently reported from Gorakhpur district in Uttar Pradesh. Scrub typhus is one of the predominant aetiological agents for these cases. In order to delineate the extent of the background of scrub typhus seroprevalence and the associated risk factors at community level, serosurveys during both lean and epidemic periods (phase 1 and phase 2, respectively) of AES outbreaks were conducted in this region. Methods: Two community-based serosurveys were conducted during lean (April-May 2016) and epidemic AES (October-November 2016) periods. A total of 1085 and 906 individuals were enrolled during lean and epidemic AES periods, respectively, from different villages reporting recent AES cases. Scrub typhus-seronegative individuals (n=254) during the lean period were tested again during the epidemic period to estimate the incidence of scrub typhus. Results: The seroprevalence of Orientia tsutsugamushi during AES epidemic period [immunoglobulin (Ig) IgG: 70.8%, IgM: 4.4%] was high as compared to that of lean AES period (IgG: 50.6%, P <0.001; IgM: 3.4%). The factors independently associated with O. tsutsugamushi positivity during lean AES period were female gender, illiteracy, not wearing footwear, not taking bath after work whereas increasing age, close contact with animals, source of drinking water and open-air defecation emerged as additional risk factors during the epidemic AES season. IgM positivity was significantly higher among febrile individuals compared to those without fever (7.7 vs. 3.5%, P=0.006). The seroincidence for O. tsutsugamushi was 19.7 per cent, and the subclinical infection rate was 54 per cent. Interpretation & conclusions: The community-based surveys identified endemicity of O. tsutsugamushi and the associated risk factors in Gorakhpur region. The findings will be helpful for planning appropriate interventional strategies to control scrub typhus.

Rotavirus gastroenteritis in Indian children < 5 years hospitalized for diarrhoea, 2012 to 2016.

BACKGROUND: In 2016, the Government of India introduced the oral rotavirus vaccine (ROTAVAC, Bharat Biotech, India) in 4 states of India as part of the Universal Immunization Programme, and expanded to 5 more states in 2017. We report four years of data on rotavirus gastroenteritis in hospitalized children < 5 years of age prior to vaccine introduction. METHODS: Children from 7 sites in southern and northern India hospitalized for diarrhoea were recruited between July 2012 and June 2016. Stool samples were screened for rotavirus using enzyme immunoassay (EIA). The EIA positive samples were genotyped by reverse-transcription polymerase chain reaction. RESULTS: Of the 5834 samples from the 7 sites, 2069 (35.5%) were positive for rotavirus by EIA. Genotyping was performed for 2010 (97.1%) samples. G1P[8](56.3%), G2P[4](9.1%), G9P[4](7.6%), G9P[8](4.2%), and G12P[6](3.7%) were the common genotypes in southern India and G1P[8](36%), G9P[4](11.4%), G2P[4](11.2%), G12P[6](8.4%), and G3P[8](5.9%) in northern India. CONCLUSIONS: The study highlights the high prevalence of rotavirus gastroenteritis in India and the diversity of rotavirus genotypes across different geographical regions. Pre- vaccine surveillance data is necessary to evaluate the potential change in admission rates for gastroenteritis and circulating rotavirus genotypes after vaccine introduction, thus assessing impact.

Safety monitoring of ROTAVAC vaccine and etiological investigation of intussusception in India: study protocol.

BACKGROUND: ROTAVAC, an indigenous rotavirus vaccine, was introduced in the universal immunization program of India in four states in 2016 and expanded to five more states in 2017. The clinical trial on efficacy of ROTAVAC did not detect an increased risk of intussusception, but the trial was not large enough to detect a small risk. This protocol paper describes the establishment and implementation of a surveillance system to monitor the safety of rotavirus vaccine and investigate the potential infectious etiologies of intussusception. METHODS: This is a multi-centric hospital-based active surveillance being conducted at 28 hospitals in nine states of India. Data gathered from surveillance will be used to assess the risk of intussusception after ROTAVAC administration and to determine the infectious etiologies of intussusception. For safety assessment of ROTAVAC vaccine, children aged less than two years with intussusception admitted at the sentinel hospitals are enrolled into surveillance, a case report form completed, and a copy of the vaccination card obtained. The risk of intussusception following rotavirus vaccination will be assessed using a self-controlled case-series design. The investigation for potential infectious etiologies of intussusception is through a matched case-control design. Children enrolled for the safety assessment serve as cases and for each case, an age, gender and location matched control is enrolled within 30 days of case enrollment. Stool specimens are obtained from cases and controls. All forms and specimens are sent to the referral laboratory for data entry, analysis, multiplexed molecular testing, and storage. DISCUSSION: Anticipated public health benefits of this surveillance include the generation of information useful to national government on safety of vaccine and to make future decisions on vaccine use through risk-benefit analysis. Investigating infectious agents may help to determine the potential infectious etiologies of intussusception.