Date of Award

2-11-2022

Degree Type

Thesis

Degree Name

PhD in Health Sciences

First Advisor

Dr Rumina Hasan

Second Advisor

Dr Zafar Fatmi

Third Advisor

Dr Najeeha Iqbal

Department

Community Health Sciences

Abstract

Pneumococcus is one of the leading causes of mortality and morbidity worldwide in both children and adults. It is a leading cause of pneumonia, of which there were 7·1 million episodes in Pakistan in 2015, leading to around 64,000 deaths in children under five years. Pakistan was one of the first countries in South Asia to introduce the ten-valent pneumococcal conjugate vaccine (PCV10) in its Expanded Program on Immunization (EPI) in October 2012 as a 3+0 schedule without catchup immunisation.
The introduction of conjugate vaccines in a country’s immunisation program has been shown to decrease the burden of pneumococcal disease in the group targeted for vaccination, i.e., children under five years of age and older children and adults. This is mediated by the effect of vaccines in decreasing the carriage of pneumococcus in the nasopharynx of healthy individuals, thereby reducing community transmission.
In this study, we investigated changes in the pneumococcal carriage and serotype distribution in children 0-2 years of age in a rural population of Matiari, Pakistan, in the years following the introduction of PCV10. We compared these yearly rates with a carriage survey done in the same population in Jan/Feb 2013 after adjusting for differences in age distribution. We explored socio-demographic and clinical characteristics predicting overall and vaccine type (VT) carriage and described antimicrobial susceptibility patterns for the carried serotypes. Between 2014 to 2018, 3140 nasopharyngeal samples were collected from children less than two years of age residing in district Matiari of the Sindh province. For isolation of pneumococcal colonies, we performed culture on sheep blood agar At the Infectious Disease Research Laboratory (IDRL), Aga Khan University. Multiplex PCR was performed to determine individual serotypes using standardised CDC methods. Vaccine type (VT) carriage was defined as the cumulative frequency of all PCV10 specific serotypes divided by the number of nasopharyngeal swabs collected. Antimicrobial susceptibility was determined for nine common antimicrobials using the Kirby-Bauer disk diffusion method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. A modified Halloran model was used to estimate the population-level effects of the vaccine on nasopharyngeal carriage and compare VT carriage rates among various population compartments according to their vaccination status. Multivariable logistic regression analysis was done to determine the risk factors associated with VT carriage. Overall pneumococcal carriage declined from 80.8% (95% CI 77.8, 83.5) in study year 1 to 72.8% (95% CI 69.6, 75.9) in study year 4. Vaccine type carriage decreased from 16.1% (95% CI 13.6, 18.9) in 2014/15 to 9.6% in 2017/1895% CI 7.7, 11.9) in our study sample and from 19.9% (95% CI 16.8, 23.3) to 13.2% among isolates. In the 4-11 months age group VT carriage decreased from 26.7% (95% CI 21.0, 33.0) in the pre-PCV period (2013) to 9.6% (95% CI 7.1, 12.6) in 2017/18. Verbal or card verified vaccine coverage for 3 doses of PCV10 increased from 41·0% (95% CI 37.5, 44.6) in 2014/15 to 68·4% (95% CI 65.1, 71.6) in 2017/18. From 2014/15 to 2017/8, a decline was observed in serotypes 6B, 9V/9A,19F, 23F and 6A. However, the reduction was statistically significant for only 9V/9A 2.9% (95% CI, 1.8,4.3) in 2014/15 to 0.6 (95% CI 0.2,1.4) in 2017/18. When restricting to age group 4-11 months and comparing with the prevaccine introduction carriage survey from 2013, the decline was statistically significant for only 23F, i.e., 10.2% (95%CI 6.6,14.9) in 2013 to 3.3% (95%CI 1.9,5.3) in 2017/18. VT carriage in those who did not receive any dose of PCV10 declined from 17.4% (95%CI 13.1,22.5) in 2014/15 to 10.4% (95%CI 4.6,19.4) in 2017/18.
The direct effect varied from year to year, and the pooled estimate for the study duration was 32.8% (95%CI 14.7,47.0) when comparing those who received zero doses versus those who received three doses. Pooled estimates for indirect, and total effect were 46.5% (95%CI 39.7,53.2) and 54.9% (95% CI 52.5,57.3) respectively. In the multivariable analysis, factors associated with VT carriage included primary wage earner’s education, 1-5 years (OR 0.7, 95%CI 0.5,0.9 when compared to no education), history of cough in the past two weeks (OR 1.3 95% CI 1.0 – 1.7) and having received three doses of PCV10 (OR 0.6 95% CI 0.4 – 0.8). In the multivariable analysis for factors associated with the overall carriage, primary caretaker education 6-10 years (OR 0.6, 95% CI 0.4 – 0.9 when compared to no education), history of outpatient visits in last one months (OR 0.7, 95% CI 0.5 – 0.9 for one visit and OR 0.6, 95% CI 0.5 – 0.8 for two visits), history of runny nose in last two weeks (OR 1.6, 95% CI .3 – 2.0), year of enrollment (OR 0.7, 95% CI 0.5 – 0.9 for 2015/16, OR 0.7, 95% CI 0.5 – 1.0 for 2016/17 and OR 0.5, 95% CI 0.5 – 0.8 for 2017/18 when compared to 2014/15) and average monthly temperature (OR 0.9, 95% CI 0.9 – 1.0) were found to be significantly associated. A high degree of non-susceptibility was observed for cotrimoxazole over the study period (88.4%), while non-susceptibility for erythromycin increased from 20% to 30.8%, which could be accounted for by the increase in serotype 19A. All isolates were susceptible to vancomycin.
In conclusion, the introduction of PCV10 into the EPI has resulted in significant declines in VT carriage among both vaccinated and unvaccinated children in Matiari, thus demonstrating herd protection. Prevalence for PCV13 specific serotype 19A has increased over time with a concomitant increase in resistance to erythromycin. This study shows the effect of PCV10 in decreasing VT carriage rate in a post-introduction era and forms the baseline for further evaluating the recently introduced PCV13 in Pakistan’s EPI.

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