Muhammad Atif Habib

Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials

BACKGROUND Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia. METHODS We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18-45 years, children aged 24-59 months, older infants aged 9-12 months, and infants aged 6-8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267. FINDINGS 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67-190] to 208 U/mL [117-369]), children (201 U/mL [138-294] to 368 U/mL [234-580]), and older infants (179 U/mL [129-250] to 249 U/mL [130-477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33-94] to 63 U/mL [35-114] in adults, from 23 U/mL [15-34] to 51 U/mL [34-76] in children, and from 21 U/mL [14-31] to 22 U/mL [14-33] in older infants). Immune response in infants aged 6-8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16-28] vs 2.88 U/mL [1.95-4.25]), but not Pakistani (3.76 U/mL [2.77-5.08] vs 2.77 U/mL [2.1-3.66]), infants. Vi-CRM197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies. INTERPRETATION Vi-CRM197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO. FUNDING Sclavo Vaccines Association and Regione Toscana.

Lessons and implications from a mass immunization campaign in squatter settlements of Karachi, Pakistan: an experience from a cluster-randomized double-blinded vaccine trial [NCT00125047].

ObjectiveTo determine the safety and logistic feasibility of a mass immunization strategy outside the local immunization program in the pediatric population of urban squatter settlements in Karachi, Pakistan.MethodsA cluster-randomized double blind preventive trial was launched in August 2003 in 60 geographic clusters covering 21,059 children ages 2 to 16 years. After consent was obtained from parents or guardians, eligible children were immunized parenterally at vaccination posts in each cluster with Vi polysaccharide or hepatitis A vaccine. Safety, logistics, and standards were monitored and documented.ResultsThe vaccine coverage of the population was 74% and was higher in those under age 10 years. No life-threatening serious adverse events were reported. Adverse events occurred in less than 1% of all vaccine recipients and the main reactions reported were fever and local pain. The proportion of adverse events in Vi polysaccharide and hepatitis A recipients will not be known until the end of the trial when the code is broken. Throughout the vaccination campaign safe injection practices were maintained and the cold chain was not interrupted. Mass vaccination in slums had good acceptance. Because populations in such areas are highly mobile, settlement conditions could affect coverage. Systemic reactions were uncommon and local reactions were mild and transient. Close community involvement was pivotal for information dissemination and immunization coverage.ConclusionThis vaccine strategy described together with other information that will soon be available in the area (cost/effectiveness, vaccine delivery costs, etc) will make typhoid fever control become a reality in the near future.

A comparison of disease caused by Shigella and Campylobacter species: 24 months community based surveillance in 4 slums of Karachi, Pakistan.

Despite the efforts of the international community diarrheal diseases still pose a major threat to children in children less than five years of age. Bacterial diarrhea has also emerged as a public health concern due to the proliferation of drug resistant species in many parts of the world. There is a paucity of population-based data about the incidence of shigellosis and Campylobacter infections in Pakistan. We report country specific results for Shigella diarrhea that were derived from a multicenter study conducted in six Asian countries. Disease surveillance was conducted over a 24 month period in urban slums of Karachi, Pakistan, a city with a population of 59,584. Cases were detected through passive detection in study treatment centers. Stool specimens or rectal swabs were collected from all consenting patients. Between January 2002 and December 2003 10,540 enteric infection cases were detected. The incidence rate of treated diarrhea in children under 5 was 488/1000/year. In children, 5 years and older, the diarrhea rate was 22/1000/year. 576 (7%) Campylobacter isolates were detected. The pre-dominant Campylobacter species was C. jenuni with an increase of 29/1000 year in children under 5 years. Shigella species were isolated from 394 of 8032 children under 5 years of age. Shigella flexneri was the dominant species (10/1000/year in children under 5 years) followed by Shigella sonnei (3.9/1000/year), Shigella boydii (2.0/1000/year) and Shigella dysenteriae (1.3/1000/year). Shigellosis and Campylobacter infection rates peaked during the second year of life. The incidence rate of shigellosis increased in old age but such a trend was not observed in Campylobacter infections. Of 394 shigellosis patients 123 (31%) presented with dysentery in contrast to only 54 (9%) of 576 patients with Campylobacter infections (p<0.001). Both Campylobacter infections and shigellosis are common in community settings of Pakistan but shigellosis presented more frequently with abdominal pain and dysentery than Campylobacter infections indicating that shigellosis may be a more severe illness than Campylobacter infections. Due to the increased and disease severity, drug resistant shigella have become a significant health problem; moreover it is a disease of poor and impoverished people who do not have the access to standard water and sanitary conditions, health care services or optimal treatment. In the face of these facts it is empirically important to develop a low cost effective vaccine that can protect these populations for a longer duration.

Prevalence and Predictors of Iron Deficiency Anemia in Children under Five Years of Age in Pakistan, A Secondary Analysis of National Nutrition Survey Data 2011–2012

Background Iron deficiency Anemia (IDA) in children is a recognized public health problem that impacts adversely on child morbidity, mortality and impairs cognitive development. In Pakistan information on the true prevalence and predictors of IDA is limited. This study sought to investigate IDA in children under five years of age using data from a nationally representative stratified cross-sectional survey. Methods Secondary analysis was performed on the National Nutrition Survey in Pakistan 2011–2012. We used a pre-structured instrument to collect socio demographic and nutritional data on mothers and children. We also collected Anthropometric measurements and blood samples for micronutrient deficiencies. IDA was defined as having both haemoglobin levels of <110 g/L and ferritin levels of < 12 μg/L. Data analysis was performed by applying univariate and multivariate techniques using logistic regression through SPSS. Findings A total of 7138 children aged between 6–59 months were included in the analysis. The prevalence of IDA was 33.2%. In multivariate regression analysis adjusted odds ratios (AOR) were calculated. Age < 24 months (AOR 1.40, 95% CI 1.18–1.55 p <0.05), stunting (AOR 1.42 CI 1.23–1.63 p<0.05), presence of clinical anemia (AOR 5.69 CI 4.93–6.56 p<0.05), having a mother with IDA (AOR 1.72 CI 1.47–2.01 p<0.05) and household food insecurity (AOR 1.20 CI 1.10–1.40 P<0.05) were associated with IDA. Living in a rural area (AOR 0.77 CI 0.65–0.90 p<0.05) and being a female child (AOR 0.87 CI 0.76–0.98 p<0.05) were associated with reduced odds of IDA. Conclusion The prevalence of IDA amongst Pakistani children represents a moderate burden that disproportionately affects the youngest, growth retarded children, affected children are more likely to have mothers with IDA and live in areas where food security is lacking. National efforts to alleviate the burden of IDA should involve both short term vertical programs such as iron supplementation and long term horizontal programs including wheat flour fortification.

A study to evaluate the acceptability, feasibility and impact of packaged interventions (“Diarrhea Pack”) for prevention and treatment of childhood diarrhea in rural Pakistan

BackgroundDiarrhea remains one of the leading public health issues in developing countries and is a major contributor in morbidity and mortality in children under five years of age. Interventions such as ORS, Zinc, water purification and improved hygiene and sanitation can significantly reduce the diarrhea burden but their coverage remains low and has not been tested as packaged intervention before. This study attempts to evaluate the package of evidence based interventions in a “Diarrhea Pack” through first level health care providers at domiciliary level in community based settings. This study sought to evaluate the acceptability, feasibility and impact of diarrhea Pack on diarrhea burden.MethodsA cluster randomized design was used to evaluate the objectives of the project a union council was considered as a cluster for analysis, a total of eight clusters, four in intervention and four in control were included in the study. We conducted a baseline survey in all clusters followed by the delivery of diarrhea Pack in intervention clusters through community health workers at domiciliary level and through sales promoters to health care providers and pharmacies. Four quarterly surveillance rounds were conducted to evaluate the impact of diarrhea pack in all clusters by an independent team of Field workers.ResultsBoth the intervention and control clusters were similar at the baseline but as the study progress we found a significant increase in uptake of ORS and Zinc along with the reduction in antibiotic use, diarrhea burden and hospitalization in intervention clusters when compared with the control clusters. We found that the Diarrhea Pack was well accepted with all of its components in the community.ConclusionThe intervention was well accepted and had a productive impact on the uptake of ORS and zinc and reduction in the use of antibiotics. It is feasible to deliver interventions such as diarrhea pack through community health workers in community settings. The intervention has the potential to be scaled up at national level.

Community engagement and integrated health and polio immunisation campaigns in conflict-affected areas of Pakistan: a cluster randomised controlled trial

Summary Background Pakistan faces huge challenges in eradicating polio due to widespread poliovirus transmission and security challenges. Innovative interventions are urgently needed to strengthen community buy-in, to increase the coverage of oral polio vaccine (OPV) and other routine immunisations, and to enhance immunity through the introduction of inactivated polio vaccine (IPV) in combination with OPV. We aimed to evaluate the acceptability and effect on immunisation coverage of an integrated strategy for community engagement and maternal and child health immunisation campaigns in insecure and conflict-affected polio-endemic districts of Pakistan. Methods We did a community-based three-arm cluster randomised trial in healthy children aged 1 month to 5 years that resided within the study sites in three districts of Pakistan at high risk of polio. Clusters were randomly assigned by a computer algorithm using restricted randomisation in blocks of 20 by an external statistician (1:1:1) to receive routine polio programme activities (control, arm A), additional interventions with community outreach and mobilisation using an enhanced communication package and provision of short-term preventive maternal and child health services and routine immunisation (health camps), including OPV (arm B), or all interventions of arm B with additional provision of IPV delivered at the maternal and child health camps (arm C). An independent team conducted surveys at baseline, endline, and after each round of supplementary immunisation activity for acceptability and effect. The primary outcome measures for the study were coverage of OPV, IPV, and routine extended programme on immunisation vaccines and changes in the proportion of unvaccinated and fully vaccinated children. This trial is registered with ClinicalTrials.gov, number NCT01908114. Findings Between June 4, 2013, and May 31, 2014, 387 clusters were randomised (131 to arm A, 127 to arm B, and 129 to arm C). At baseline, 28 760 children younger than 5 years were recorded in arm A, 30 098 in arm B, and 29 126 in arm C. 359 clusters remained in the trial until the end (116 in arm A, 120 in arm B, and 123 in arm C; with 23 334 children younger than 5 years in arm A, 26 110 in arm B, and 25 745 in arm C). The estimated OPV coverage was 75% in arm A compared with 82% in arm B (difference vs arm A 6·6%; 95% CI 4·8–8·3) and 84% in arm C (8·5%, 6·8–10·1; overall p<0·0001). The mean proportion of routine vaccine doses received by children younger than 24 months of age was 43% in arm A, 52% in arm B (9%, 7–11) and 54% in arm C (11%, 9–13; overall p<0·0001). No serious adverse events requiring hospitalisation were reported after immunisation. Interpretation Despite the challenges associated with the polio end-game in high-risk, conflict-affected areas of Pakistan, a strategy of community mobilisation and targeted community-based health and immunisation camps during polio immunisation campaigns was successful in increasing vaccine coverage, including polio vaccine coverage. Funding Bill & Melinda Gates Foundation.

Knowledge and perceptions of polio and polio immunization in polio high-risk areas of Pakistan

Pakistan and Afghanistan remain the only countries where polio is endemic, and Pakistan reports the most cases in the world. Although the rate is lower than in previous years, the situation remains alarming. We conducted a mixed methods study in high-risk areas of Pakistan to identify knowledge, attitudes, and practices of target populations about polio vaccine and its eradication, and to estimate coverage of routine immunization and oral polio vaccine. We surveyed 10,685 households in Karachi, 2522 in Pishin, and 2005 in Bajaur. Some knowledge of polio is universal, but important misconceptions persist. The findings of this study carry strategic importance for program direction and implementation.

Improved accessibility of emergency obstetrics and newborn care(EmONC) services for maternal and newborn health: a community based project

BackgroundEvery year an estimated three million neonates die globally and two hundred thousand of these deaths occur in Pakistan. Majority of these neonates die in rural areas of underdeveloped countries from preventable causes (infections, complications related to low birth weight and prematurity). Similarly about three hundred thousand mother died in 2010 and Pakistan is among ten countries where sixty percent burden of these deaths is concentrated. Maternal and neonatal mortality remain to be unacceptably high in Pakistan especially in rural areas where more than half of births occur.Method/DesignThis community based cluster randomized controlled trial will evaluate the impact of an Emergency Obstetric and Newborn Care (EmONC) package in the intervention arm compared to standard of care in control arm. Perinatal and neonatal mortality are primary outcome measure for this trial. The trial will be implemented in 20 clusters (Union councils) of District Rahimyar Khan, Pakistan. The EmONC package consists of provision of maternal and neonatal health pack (clean delivery kit, emollient, chlorhexidine) for safe motherhood and newborn wellbeing and training of community level and facility based health care providers with emphasis on referral of complicated cases to nearest public health facilities and community mobilization.DiscussionEven though there is substantial evidence in support of effectiveness of various health interventions for improving maternal, neonatal and child health. Reduction in perinatal and neonatal mortality remains a big challenge in resource constrained and diverse countries like Pakistan and achieving MDG 4 and 5 appears to be a distant reality. A comprehensive package of community based low cost interventions along the continuum of care tailored according to the socio cultural environment coupled with existing health force capacity building may result in improving the maternal and neonatal outcomes.The findings of this proposed community based trial will provide sufficient evidence on feasibility, acceptability and effectiveness to the policy makers for replicating and scaling up the interventions within the health systemTrial registrationClinicalTrial.gov NCT01751945

A mixed methods study to assess the effectiveness of food-based interventions to prevent stunting among children under-five years in Districts Thatta and Sujawal, Sindh Province, Pakistan: study protocol

BackgroundMaternal and child malnutrition is widely prevalent in low and middle income countries. In Pakistan, widespread food insecurity and malnutrition are the main contributors to poor health, low survival rates and the loss of human capital development. The nutritional status trends among children exhibit a continuous deteriorating with rates of malnutrition exceeding the WHO critical threshold. With the high prevalence of maternal and child malnutrition, it is important to identify effective preventative approaches, especially for reducing stunting in children under-five years of age. The primary aim of this study is to assess the effectiveness of food-based interventions to prevent stunting in children under-five years.MethodsA mixed methods study design will be conducted to evaluate the effectiveness of food-based interventions to prevent stunting among children under-five years in districts Thatta and Sujawal, Sindh Province, Pakistan. The study will include cross sectional surveys, a community-based cluster randomized controlled trial and a process evaluation. The study participants will be pregnant women, lactating mothers and children under-five years. The cross-sectional surveys will be conducted with 7360 study participants at baseline and endline. For the randomized control trial, 5000 participants will be recruited and followed monthly for compliance of food-based supplements, dietary diversity, pregnancy outcomes, and maternal and child morbidity and mortality. Anthropometric measurements and hemoglobin levels will be measured at baseline, quarterly and at endline. The interventions will consist of locally produced lipid-based nutrient supplement (Wawamum) for children 6–23 months, micronutrient powders for children 24–59 months, and wheat soya blends for pregnant and lactating mothers. Government lady health workers will deliver interventions to participants. The effectiveness of the project will be measured in terms of the impact of the proposed interventions on stunting, nutritional status, micronutrient deficiencies, and other key indicators of the participants. The process evaluation will assess the acceptability, feasibility and potential barriers of project implementation through focus group discussions, key informant interviews and household surveys. Data analysis will be conducted using STATA version 12.DiscussionThere is considerable evidence on the effectiveness of food-based interventions in managing stunting in developing countries. However, these studies do not account for the local environmental factors and widespread nutrient deficiencies in Pakistan. These studies are often conducted in controlled environments, where the results cannot be generalized to programs operating under field conditions. The findings of this study will provide sufficient evidence to develop policies and programs aimed to prevent stunting in children 6–59 months and to improve maternal and child health and growth outcomes in poor resource settings.Trial registrationNCT02422953. Registered on April 15, 2015.

Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013.

BACKGROUND Considering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan. METHODS A five-arm randomized clinical trial was conducted among children (6-24months, 5-6years and 10-11years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV+vitamin A, and bOPV+IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28days after intervention were assessed. RESULTS The baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95-99%) compared with bOPV only arms (11-43%), [p<0.001]; Vitamin A was not associated with improved immune response. Immune response rates in the IPV only arm and IPV+bOPV arm were similar [p>0.5]. CONCLUSION IPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan.