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The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001–11: a retrospective analysis

Summary Background Pakistan and Afghanistan are two of the three remaining countries yet to interrupt wild-type poliovirus transmission. The increasing incidence of poliomyelitis in these countries during 2010–11 led the Executive Board of WHO in January, 2012, to declare polio eradication a “programmatic emergency for global public health”. We aimed to establish why incidence is rising in these countries despite programme innovations including the introduction of new vaccines. Methods We did a matched case-control analysis based on a database of 46 977 children aged 0–14 years with onset of acute flaccid paralysis between Jan 1, 2001, and Dec 31, 2011. The vaccination history of children with poliomyelitis was compared with that of children with acute flaccid paralysis due to other causes to estimate the clinical effectiveness of oral poliovirus vaccines (OPVs) in Afghanistan and Pakistan by conditional logistic regression. We estimated vaccine coverage and serotype-specific vaccine-induced population immunity in children aged 0–2 years and assessed their association with the incidence of poliomyelitis over time in seven regions of Afghanistan and Pakistan. Findings Between Jan 1, 2001, and Dec 31, 2011, there were 883 cases of serotype 1 poliomyelitis (710 in Pakistan and 173 in Afghanistan) and 272 cases of poliomyelitis serotype 3 (216 in Pakistan and 56 in Afghanistan). The estimated clinical effectiveness of a dose of trivalent OPV against serotype 1 poliomyelitis was 12·5% (95% CI 5·6–18·8) compared with 34·5% (16·1–48·9) for monovalent OPV (p=0·007) and 23·4% (10·4–34·6) for bivalent OPV (p=0·067). Bivalent OPV was non-inferior compared with monovalent OPV (p=0·21). Vaccination coverage decreased during 2006–11 in the Federally Administered Tribal Areas (FATA), Balochistan, and Khyber Pakhtunkhwa in Pakistan and in southern Afghanistan. Although partially mitigated by the use of more effective vaccines, these decreases in coverage resulted in lower vaccine-induced population immunity to poliovirus serotype 1 in FATA and Balochistan and associated increases in the incidence of poliomyelitis. Interpretation The effectiveness of bivalent OPV is comparable with monovalent OPV and can therefore be used in eradicating serotype 1 poliomyelitis whilst minimising the risks of serotype 3 outbreaks. However, decreases in vaccination coverage in parts of Pakistan and southern Afghanistan have severely limited the effect of this vaccine. Funding Poliovirus Research subcommittee of WHO, Royal Society, and Medical Research Council.

A matched case-control design was used to estimate the clinical efficacy of the trivalent, bivalent and monovalent oral polio vaccines (OPVs) against poliomyelitis caused by type 1 and 3 poliovirus. A case of poliomyelitis was defined as a child with acute flaccid paralysis (AFP) where wild-type poliovirus was isolated from at least one stool sample, and a control was randomly selected from children in the AFP database where no poliovirus (wild or vaccine derived) was isolated ('non-polio AFP'). Children with poliomyelitis were matched using a 1:1 ratio with controls that were randomly selected from the database of children with non-polio AFP. Matching was used to minimise the difference in exposure to wild poliovirus between cases and controls. Cases and controls were matched by age and date of onset of paralysis (within 90 days), and by district of residence in Pakistan and province of residence in Afghanistan (provinces in Afghanistan are similar in population size to districts in Pakistan). The number of doses of trivalent OPV received through routine immunisation services is likely to reflect socioeconomic status, education level and access to healthcare, and therefore presumably exposure to faecal-oral pathogens, including poliovirus. Preliminary analysis showed that exact matching by the number of doses of trivalent OPV received through routine immunisation services only reduced the variance in the estimates of vaccine efficacy when compared to matching that did not include information about routine doses. We therefore additionally included this matching criterion. Sensitivity of the estimates of vaccine efficacy to all matching criteria was assessed by univariate sensitivity analysis.
Conditional logistic regression was used to estimate the odds of paralysis by poliovirus types 1 and 3 as described in the main text. Differences in vaccine efficacy between regions were explored by including interaction terms between location and the number of vaccine doses in the model and examining the log-likelihood of each model.
The random allocation of controls to cases contributed to variance in the estimated vaccine efficacy. The relative contribution of individual matched pairs was assessed using the 'dfbeta' statistic, which can be used to identify observations which have a unusually large contribution to the estimate of the coefficient in the regression model. 1 Matched pairs were excluded if the absolute value of the 'dfbeta' statistic was more than ten times the mean value of all matched pairs in the data. To account for any additional variability from the matching process, 10 sets of randomly chosen matched case-control pairs were produced and vaccine efficacy was estimated for each set. We have presented the matched set providing the most similar estimate of efficacy to the average value from all matched sets. The statistical analysis was carried out using STATA (version 11.0, TX, USA).
During preliminary analysis it was found that there were insufficient cases of poliomyelitis caused by serotype 3 to accurately estimate vaccine efficacy. We therefore provide vaccine efficacy and population immunity estimates for serotype 1 only.

Assessment of the accuracy of caregiver recall of vaccination history
We carried out a number of analyses in an attempt to assess the validity and consistency of the reported number of vaccine doses received through routine and supplementary immunisation activities by each child in the AFP database. The reported number is based on verbal recall of the caregiver at the time of initial interview by the investigating medical officer. Vaccination cards were also used by medical officers to inform the vaccination history of the child. However, these cards were only available for 25% of children and contain information on doses of OPV received through routine immunisation only.
Firstly, we examined the correlation between the caregiver's report of the number of OPV doses received through supplementary immunisation activities (SIA) and the administrative records of the SIA that took place in the district of residence during the child's lifetime. Secondly, we examined the relationship between the reported number of vaccine doses received and the odds of paralytic poliomyelitis to test for an expected geometric relationship, whereby each dose is associated with a fixed probability of vaccine replication ('take') and associated vaccineinduced protection. Finally, we examined the relationship between the incidence of poliomyelitis in a district and estimated vaccine induced immunity based on the reported vaccination history of AFP cases.

Assessment of the accuracy of caregiver recall of vaccination history
Supplementary Web Appendix figure 1 plots the relationship between the number of doses of OPV received through SIA reported by the caregiver of children with non-polio AFP compared with that expected based on the SIA schedule. There is considerable agreement (Pearson's correlation coefficient 0.638) and this is particularly apparent when the number of OPV doses according to the SIA calendar is less than 10. There is evidence for a preference for the caregiver to report 'favoured' numbers at higher dose numbers, in particular 7, 10, 12, 15 and 20 doses.
The estimated vaccine efficacy by reported number of doses of each vaccine was consistent with a constant perdose probability of vaccine 'take' (likelihood ratio test did not reject a model of constant vaccine take, P-value=0.22; Web Appendix Figure 2). Dose reporting is therefore consistent with the expected mode of action of OPV.
The annual incidence of poliomyelitis associated with serotype 1 wild-type poliovirus was correlated with the estimated vaccine-induced population immunity to this serotype by district (Pakistan) or province (Afghanistan) (Spearman's ranked correlation coefficient -0·11; Web Appendix Figure 3). Population immunity based on caregiver recall of the number of OPV doses received by children with non-polio AFP therefore appears to be a reasonable predictor of susceptibility to poliomyelitis in the community.