Background for Adverse Events Following Immunization:
In 2018, the World Health Organization reported that despite the availability of safe and effective measles containing vaccine first dose, Nigeria still remained the country with the highest burden of measles globally resulting from over 2.44 million unvaccinated children.(1) Nigeria conducted a national measles supplemental campaign between September 2017 and April 2018. By the end of week 52 of December 2018, the Nigeria Center for Disease Control had reported 17412 suspected measles cases with 1345 laboratory confirmed cases and 128 deaths in all 36 States and Federal Capital Territory (FCT) compared with 21,974 suspected measles cases with 1609 laboratory confirmed cases and 117 deaths at the same period in 2017.(2) Even though rates seems to reduce following vaccination campaigns, Nigerian children still struggle with epidemics of measles that occurs soon after. Numerous studies conducted around the globe reveal that one of the major reasons for non - vaccination of eligible children by their parents and caregivers is the fear of developing an adverse event following vaccination. (3-7)
The World Health Organization defines an Adverse Event Following Immunization (AEFI) as any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine.(8) The adverse event may be any unfavorable, unintended sign, abnormal laboratory finding, or symptom or disease.(8) Different countries have recorded different rates and patterns of AEFI during supplemental vaccination campaigns and following active and passive surveillance. Adverse events following such campaigns has led to increasing concerns of not just the public but also the medical community and parents alike. AEFI must be carefully documented and managed properly in order to increase the confidence of the public in accepting vaccinations for all eligible children.(9)
In Africa, adverse events following immunization are under reported both by parents and healthcare workers. Parents may not have the finances to go to and from the primary health care centers or clinics to report AEFI especially the mild cases while health care workers may feel that they maybe victimized if they report too many cases of AEFI.(9) While Ghana , Cameroun and Zimbabwe reported AEFI rates ranging from 5.1% - 39%, fever and swelling at injection sites were the commonest clinical presentation among children under 5 years of age.(10-12) In Kwara, Kano and Rivers States, all in Nigeria, AEFI rates ranged from 19.3% -57% with similar clinical presentations. (13-15) Outside Africa, AEFI rates swing between two extremes: while the United States reported rates as low as 1.4 per 100000 doses, China, Oman, Australia reported differing rates of 9.2, 10.8, 14.1 and Sri Lanka as high as 129.5 cases per 100,000 doses. (16-20)
In line with the WHO Global Vaccine Action Plan for Measles elimination by 2020 and the poor national measles coverage following the UNICEF Nigeria multiple indicator coverage survey of 2016 the Federal Government of Nigeria through the National Primary Health Care Development Agency (NPHCDA) and her partners planned and implemented a national measles supplemental vaccination campaign. (9) The successful completion of this campaign witnessed the vaccination of over 35 million children in all the 36 states and the Federal Capital Territory (FCT) and a total of 19.1% of adverse events following immunization were documented nationwide. The aim of this article is to report the incidence and pattern of adverse events associated with the 2017/2018 single dose measles containing virus vaccine administered during the national measles vaccination campaign.
Materials and Methods:
Setting:
Nigeria is the most populous country in Africa and the sixth most populous in the world. She is located in Western Africa and is divided into six geopolitical regions: Northeast, Northwest, North Central, South South, South East and South West. She has 36 states and a federal capital which is located at Abuja. Each state is divided into smaller administrative units called local government areas or local councils and each LGA is further divided into political wards.
Nigeria adopted the National Programme on immunization in 1978 and has been immunizing children less than 11 months of age against vaccine preventable diseases. Measles containing vaccine 1 is given at a dose of 0.5ml subcutaneously at the left upper arm to all children at 9 months of age along with yellow fever vaccine and currently meningitis vaccine. All vaccines given to Nigerian children is sourced by the National Primary Health Care Development Agency.
Survey fieldwork implementation
The mass measles campaign was carried out in different phases. While the Northern region implemented in November of 2017, the Southern cluster executed in March of 2018. Reports were documented only if the adverse event occurred about 6weeks following the mass vaccination in children between 9 - 59 months. Health care providers, parents, community members and leaders were all encouraged to report every adverse event. AEFI committees were formed at all levels of government (local, state and national). At the local government levels trainings were conducted for vaccinators who formed part of each vaccination team. These vaccinators were trained to manage mild cases of AEFI using the approved and provided AEFI kits by the state. At the state level similar training were conducted for one clinician working in a secondary health facility in every local government area (LGA) to handle all serious cases of AEFI in each ward in the LGA.
Sampling Technique
The World Health Organization Expanded Programme on Immunization Survey instrument was used for this study using a stratified two stage - cluster sampling design. The sampling frame was determined from the list of enumeration areas prepared for the 2006 national population census. A total of 30 enumeration areas (EAs) were selected from the master sampling frame for each state. Following first stage sampling, complete listing of households and a mapping exercise were carried out for each selected EAs to identify households with children aged between 9 and 59 months who were eligible for second stage selection. In the second stage, selection of households to be interviewed was conducted by the National Bureau of Statistics using simple random sampling technique. Seven (7) households with eligible children were randomly selected from each of the 30 enumeration areas in every state making a total of 210 households per state. All households selected were occupied, hence participated in the study. Design weights were computed as the product of inverse probabilities of selection in the first and second stage followed by adjustment for household non-response and child non-response to get the sampling weights for households and for children, respectively. This is done to ensure that all subpopulations are equally represented.
Data Collection
There were two major sources of report. Parents reported all significant AEFI to the team supervisors (vaccine providers) who documented such cases in the ward AEFI line –listing form. These forms were subsequently returned to the local government immunization officer (LIO) who complied all AEFI cases in the ward into the LGA AEFI investigation form. The investigation forms from the different LIOs were sent to the state immunization officer (SIO). Reports were carefully screened by the SIOs and only serious cases were immediately notified to the National campaign manager by phone and later on by a full written report. The investigation form was a very important document for conducting causality assessment of the affected under-fives. The second source of adverse events reports was from the disease surveillance and notification officers (DSNOs) from all the LGAs. These officers were trained during the campaign to document cases of measles reactions seen during their active or passive surveillance activities. These reports were passed on to the LIOs who cross-checked her line –lists to avoid double entry. Finally, the LIOs passed all line-list forms to the state immunization officer who in turn notified the national campaign manager.
Reports collated from these sources were scrutinized for double entry and treatment and recovery status. These reports were subsequently reviewed by three pediatricians, two public health physicians and the National measles campaign manager. The panel classified each case event based on gender, area, age group, and zones.
Data Analysis
Data entering was done using Census and Survey Program (CSPro) software running on android computers. Data cleaning and analysis was conducted using the supplementary immunisation activity (SIA) module of Vaccination Coverage Quality Indicators (VCQI) software running on Stata version 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.). Rates of adverse events were calculated by dividing the number of events by the number of doses of the measles vaccine administered during the supplemental campaign. Ratios were also calculated for gender and area of residence.
Ethical Considerations:
Since this campaign was a National Campaign, the Federal Ministry of Health waived approval. Parents and guardians gave verbal consent for their children and wards to be vaccinated during the campaign.
Results
Nationally, the 36 states and the Federal Capital Territory recorded a total of 19.1% of adverse events following immunization in children aged 9-59 months. National data from the 2017/2018 measles vaccination campaign categorized by age group, gender, area and zone is presented here.
Table 1 reveals the categories of AEFI stratified by gender. Systemic reactions accounted for the majority of the AEFIs reported in this study. Fever was documented as the commonest AEFI among males (8.9%) and females (8.6%). Neurological events like seizures (2.5) accounted for the highest reporting ratio.
| Table 1: Number of AEFI reports and reporting ratio based on sex |
| Adverse Events |
Number of AEFI Reports (%) |
Male |
Female |
Male : Female Ratio |
Injection Site Reactions |
|
|
|
Pain at Injection site |
7.4 |
6.4 |
1.9 |
Joint or muscle pain |
2.2 |
2.3 |
1.0 |
Lump at injection site |
0.4 |
0.3 |
1.3 |
Systemic Reactions |
|
|
|
Fever |
8.9 |
8.6 |
1.0 |
Headache |
0.5 |
0.6 |
0.8 |
General rash |
1.4 |
1.1 |
1.3 |
Extreme drowsiness and fainting |
0.1 |
0.0 |
- |
Fussiness, irritability and crying |
0.6 |
0.6 |
1.0 |
Early bruising or bleeding |
0.1 |
0.1 |
1.0 |
Allergic Events |
|
|
|
Itchiness especially feet and hands |
1.1 |
0.7 |
1.6 |
Hives |
0.1 |
0.1 |
1.0 |
Neurological events |
|
|
|
Problems with hearing or vision |
0.2 |
0.1 |
2.0 |
Seizure |
0.5 |
0.2 |
2.5 |
Confusion or drowsiness |
0.0 |
0.1 |
0.0 |
Table 2 highlights the categories of AEFI stratified by area of residence. This study reported that injection site reactions (9.8%) and fever (7.7%) were commoner in children from rural areas. However, allergic reactions like hives and general rash were commoner in the urban areas with reporting ratios of 3.0 and 2.3 respectively.
| Table 2: Number of AEFI reports and reporting ratio based on area |
| Adverse Events |
Number of AEFI Reports (%) |
Urban |
Rural |
Urban : Rural Ratio |
Injection Site Reactions |
|
|
|
Pain at Injection site |
5.2 |
7.7 |
0.6 |
Joint or muscle pain |
1.5 |
2.5 |
0.6 |
Lump at injection site |
0.5 |
0.3 |
1.7 |
Systemic Reactions |
|
|
|
Fever |
6.1 |
9.8 |
0.6 |
Headache |
0.3 |
0.6 |
0.5 |
General rash |
2.1 |
0.9 |
2.3 |
Extreme drowsiness and fainting |
0.0 |
0.1 |
- |
Fussiness, irritability and crying |
0.7 |
0.6 |
1.2 |
Early bruising or bleeding |
0.0 |
0.1 |
- |
Allergic Events |
|
|
|
Itchiness especially feet and hands |
1.0 |
0.8 |
1.3 |
Hives |
0.3 |
0.1 |
3.0 |
Neurological events |
|
|
|
Problems with hearing or vision |
0.1 |
0.2 |
0.5 |
Seizure |
0.4 |
0.4 |
1.0 |
Confusion or drowsiness |
0.1 |
0.1 |
1.0 |
Table 3 reported the categories of AEFI stratified by the age groups which revealed that injection site reactions, systemic reactions, allergy and neurological reactions were more common in the age groups 24-59 months.
| Table 3: Number of AEFI cases reported based on age group 9-59 months. |
| Adverse Events |
Number of AEFI Reports (%) |
9-11 |
12-23 |
24-59 |
Injection Site Reactions |
|
|
|
Pain at Injection site |
8.7 |
7.4 |
20.6 |
Joint or muscle pain |
2.5 |
2.3 |
6.6 |
Lump at injection site |
0.5 |
0.3 |
1.1 |
Systemic Reactions |
|
|
|
Fever |
7.8 |
9.3 |
26.1 |
Headache |
1.4 |
0.3 |
1.8 |
General rash |
1.6 |
1.2 |
3.6 |
Extreme drowsiness and fainting |
0.0 |
0.0 |
0.3 |
Fussiness, irritability and crying |
0.0 |
0.7 |
1.8 |
Early bruising or bleeding |
0.0 |
0.1 |
0.3 |
Allergic Events |
|
|
|
Itchiness especially feet and hands |
0.7 |
0.7 |
3.9 |
Hives |
0.5 |
0.2 |
0.4 |
Neurological events |
|
|
|
Problems with hearing or vision |
0.0 |
0.0 |
0.5 |
Seizure |
0.5 |
0.2 |
1.3 |
Confusion or drowsiness |
0.0 |
0.2 |
0.1 |
Figure 1 highlights the national proportion of AEFI reported following the measles vaccination campaign in Nigeria. Only 19% of children between 9-59 months of age experienced an adverse event during the supplemental activity.
 |
Fig 1: National AEFI rate reported during the MVC |
Figure 2 reports the national AEFI rates by the six geopolitical regions in Nigeria; Northeast, Northwest, Northcentral, Southeast, South south and Southwest. While the Northwest region (22.4%) had the highest proportion of AEFI, the Southewest region (14.4%) had the lowest proportion.
 |
Fig 2: Rates of AEFIs in the 6 geopolitical regions of Nigeria |
Discussion
In Nigeria, out of the 10,153 sampled children that were vaccinated during the 2017-2018 mass measles vaccination campaign, about 19.1% children encountered some adverse events. This proportion of AEFI was found to be similar to that reported in hospital studies carried out in Pudcherry, India (19%) and Kwara State, Nigeria (19.3%) but higher than the rates reported in Zhejiang Province, China (9.2%), the United Kingdom (14.9%) and Australia (5.2%) respectively.(13,17, 19,21,22) However, a study carried out in Czech Republic using pediatric general practitioners’ records of children who had received the MMR vaccine reported cases as high as 85.2%.(23) This disparity in the proportions of reported AEFI among countries could be as a result of numerous factors including programmatic errors, quality and type of vaccine.
According to the study, a higher ratio of AEFIs were reported in male children, with a male to female ratio of 1.1:1. This finding is consistent with studies carried out in Ilorin, Nigeria Czech Republic, India and Brazil, which also reported higher rates of AEFIs in boys, with a male to female rate ratio of 1.5:1, 1.1:1, 1.1:1 and 1.1:1 respectively (13,21,23,24). Contrary to this finding, a similar study carried out in Congo, United States and Australia amongst people older than 5 years showed that the ratio of reported AEFIs were more in females (female to male ratio 2:1).(16,19,25) However, there was no sex-specific difference in rates observed for children less than 11 years in Ontario, Canada.(26) While the biological basis for the gender differences observed here cannot easily be explained, immunological, hormonal, genetic and microbiota can be contributory factors to this finding.
In our study, a majority of the AEFI were reported in the Northern zones (63.5% )when compared with the Southern zone (48.9%) giving a North to South ratio of 1.3:1. A similar study done in the Zhejiang province of China also reported that a higher ratio of the AEFIs were seen in the Northern areas (Hangzhou and Ningbo) than in the southern areas with a North to South ratio of 1.8:1(17). Our study revealed that more populated zones had higher reporting rate (e.g., North Central zone), than less populated zones (South West zone). This is dissimilar to the findings in United States and Canada, where more populous areas had lower reporting ratio than less populous areas. (16,26)
The highest proportions of AEFI in this study was reported among children within the age group of 24-59 months. Similarly, majority of AEFIs reported in the China study was seen in infants more than 1 year of age (85.2%).(17) However, a study carried out in Ilorin, Nigeria reported a higher proportion (57.9%) of AEFIs among children less than 1 year (2-4 months).(13) The findings from this study is also not consistent with findings from a similar study carried out in Gerais, located in the Southeastern part of Brazil, where more than half (56.1%) of the total AEFIs reported were seen in children less than 1 year of age.(24) The reported differences in the different age groups could be as a result of the more matured immune system in older infants.
There is a risk of the occurrence of simple febrile seizures in young children between 6 months - 5 years after the administration of the combined MMR vaccine.(16) A study done in the United States of America shows that the measles constituent of the vaccine could be linked to febrile convulsions often occurring within 6 to 11 days after the first dose of MMR in children aged 12-24 months.(16) The average proportions of seizures in our study for all children aged 9-59 months was 0.4% which is similar to the 0.3% reported in Australia, and slightly more than the 0.17% reported in UK although the proportion in the UK may have been overestimated as both vaccine-related and coincidental reactions were calculated together.(19,22)
The two most common adverse reactions amongst children aged 9- 59 months in this study was fever with a proportion of 43.2% and pain at the injection site with a rate of 36.7%. This finding is consistent with the study in Puducherry, India, where fever was also reported as the most common adverse reaction (44%) followed by swelling at injection site (22%).(21) When compared with a similar study done in Ilorin, the most common AEFI discovered was local swelling at the site of injection (50.9%), resulting to about half of total AEFIs reported.(13) In the Czech Republic study also, local reactions (redness, swelling and pain) accounted for more than half (65%) of all reported adverse events.(23) However, the most common adverse reactions reported during the Australian campaign was syncopal fit 23.6%.(19) The disparity among countries in the rates or proportions of reported AEFI could be as a result of the vaccine product or immunization error related reactions.
Conclusion:
In general, there was a low proportion of adverse events reported in this study. In as much as the majority of AEFIs reported were mostly non-life-threatening reactions, there is still a need to educate care givers, health care providers and the general public about AEFIs and when and how to report a suspected event. To tackle the issue of underreporting, health providers should be encouraged to report AEFIs, so as to boost public trust in immunization programs and increase the vaccine safety profile.
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