Evaluating the Effectiveness of a Pneumococcal Immunisation Campaign in a Camp for Internally Displaced People

Study Overview
=================
Brief Summary
-----------------
Pneumococcal conjugate vaccine (PCV) is used routinely worldwide as part of infant immunisations to prevent acquisition of Streptococcus pneumoniae, the aetiologic agent responsible for a large proportion of early childhood pneumonia and invasive disease. However, PCV has seen minimal uptake in populations affected by forced displacement and humanitarian crises, where the burden of pneumococcal disease is plausibly elevated. This study seeks to generate evidence on appropriate vaccination strategies for crisis-affected populations. The investigators plan to exhaustively vaccinate children up to 15 years in a camp for displaced persons outside Hargeisa, the capital of Somaliland. The study will deliver PCV in a campaign modality, so as to achieve both short- and long-term herd immunity effects that, the investigators hypothesise, will reduce population-wide nasopharyngeal S. pneumoniae transmission and thereby protect young children from pneumococcal disease. The study will adopt a quasi-experimental design, with baseline and post-intervention surveys to evaluate changes in pneumococcal carriage, complemented by safety assessment in children aged over 2 years, for whom PCV safety data are scarce, and longitudinal data collection on incidence of pneumonia and antibiotic prescriptions in the camp.

Official Title
-----------------
Evaluating the Effectiveness of a Pneumococcal Immunisation Campaign in a Camp for Internally Displaced People: A Non-randomised, Quasi-experimental Phase IV Intervention Study

Conditions
-----------------
Pneumococcal Infections

Intervention / Treatment
-----------------
* Biological: Pneumococcal conjugate vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Resident in Digaale camp Voluntary written/thumb-printed informed consent has been provided by a parent or caretaker; Subject's parent must be able to comprehend and comply with study requirements and procedures; Subject's parents must have a readily identifiable place of residence in the study area, be available for the duration of study participation, and have a means of telephone contact Exclusion Criteria: Known hypersensitivity to any component of the vaccine, including diphtheria toxoid; History of allergic disease or history of a serious reaction to any prior vaccination or known hypersensitivity to any component of the study vaccines. This includes such reactions in older siblings and also includes all components of the Expanded Programme of Immunization vaccines; History of anaphylactic shock; Any abnormal (Grade ≥ 1) vital sign. Note: An abnormal vital sign, including fever (axillary temperature of ≥ 37.5°C), may be repeated to determine whether a subject is eligible for vaccination. A minimum of 48 hours following a documented fever must pass before the subject can be reassessed for eligibility. Any moderate or severe (Grade ≥ 2) acute illness. Note: Infants with a Grade 1 acute illness may be enrolled at the discretion of the PI. Note: Subjects with moderate or severe acute illness may return for clinical re-assessment; if the illness has sufficiently resolved, they may still qualify for vaccination. Chronic administration (defined as more than 14 consecutive days) of immunosuppressant or other immune modifying drugs prior to the administration of the study vaccine, including the use of glucocorticoids. The use of topical and inhaled glucocorticoids is not an exclusion criterion.

Ages Eligible for Study
-----------------
Minimum Age: 6 Weeks
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Before vs. after quasi-experimental study. Entire study population is offered the intervention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mass vaccination<br>Mass vaccination of children aged 6 weeks to 14 years old with pneumococcal conjugate vaccine. Children 6 weeks to 11 months old receive two doses, spaced 4 weeks apart. All other children receive a single dose. Vaccination is simultaneous, as per a campaign delivery strategy. | Biological: Pneumococcal conjugate vaccine<br>* Mass campaign offering simultaneous pneumococcal conjugate vaccination to all children aged below 15 years of age living in Digaale camp, Somaliland. Children aged below 12 months receive 2 doses of vaccine, spaced 4 weeks apart. All other children receive one dose.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children below 24 months old | The outcome is determined at the individual level, through polymerase chain reaction (PCR) microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 6 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children below 24 months old | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 12 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children below 24 months old | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 24 months, relative to baseline (pre-vaccination) | 
| Number and proportion of vaccination recipients who experience solicited local and systemic adverse events following immunisation (AEFI) | The outcome is determined at the individual level. 'Solicited' indicates that adverse events are identified by study staff using a pre-defined checklist of signs and symptoms and proactive monitoring or follow-up of vaccine recipients. AEFI will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 24.0 or later). Outcome ascertainment will occur through (i) in-person monitoring of vaccine recipients for 30 minutes after vaccine administration, and (ii) exhaustive follow-up of all vaccine recipients 7 days after vaccination, with administration of a structured questionnaire to their parents or caregivers. All AEFI will be graded using a severity scale (0 - none; 1 - mild; 2 - moderate; 3- severe; 4 - very severe; 5 - fatal), and analysis will be stratified by severity and age group (6 weeks to 11 months old, 12 to 23 months old, 24 to 59 months old, 5 to 14 years old). | within 7 days of receipt of each vaccine dose | 
| Number and proportion of vaccination recipients who experience solicited or unsolicited severe adverse events (SAE) following vaccination | The outcome is determined at the individual level. SAE are defined as any AEFI with severity >= 3. Outcome ascertainment will occur through (i) in-person monitoring of vaccine recipients for 30 min after vaccine administration, (ii) exhaustive follow-up of all vaccine recipients 7 days after vaccination, with administration of a structured questionnaire to their parents or caregivers; (iii) availability of a 24/7 phone number which caregivers of vaccine recipients will be encouraged to contact; (iv) visits to the camp's single primary healthcare facility, during each day on which vaccination takes place, to identify any children presenting for care with a SAE; and (v) availability of a 24/7 phone number which clinicians at the primary healthcare facility will be encouraged to contact. Each SAE will be followed up until resolution. Relatedness of each SAE to vaccine receipt will be classified as 'unrelated', 'unlikely', 'possible', 'probable', 'definite' and 'not assessable'. | within 7 days of receipt of each vaccine dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children and adults 24 months old or older | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 6 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children and adults 24 months old or older | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 12 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of vaccine-type Streptococcus pneumoniae serotypes in children and adults 24 months old or older | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, and include serotypes serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F and 23F. | 24 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of non-vaccine-type Streptococcus pneumoniae serotypes in children and adults | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Non-vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is not designed to provide immunity for, i.e. any serotypes other than 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. | 6 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of non-vaccine-type Streptococcus pneumoniae serotypes in children and adults | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Non-vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is not designed to provide immunity for, i.e. any serotypes other than 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. | 12 months, relative to baseline (pre-vaccination) | 
| Nasopharyngeal carriage of one or more colonies of non-vaccine-type Streptococcus pneumoniae serotypes in children and adults | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above). Non-vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is not designed to provide immunity for, i.e. any serotypes other than 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. | 24 months, relative to baseline (pre-vaccination) | 
| Mean bacteriological density of vaccine- and non-vaccine-type Streptococcus pneumoniae infections, among children and adults with at least one infecting colony in the nasopharynx | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. Bacteriological density is estimated after PCR analysis as copies per milliliter. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above), and by vaccine-type versus non-vaccine-type serotype colonies. Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, i.e. 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. Non-vaccine serotypes are defined as any other serotype. | 6 months, relative to baseline (pre-vaccination) | 
| Mean bacteriological density of vaccine- and non-vaccine-type Streptococcus pneumoniae infections, among children and adults with at least one infecting colony in the nasopharynx | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. Bacteriological density is estimated after PCR analysis as copies per milliliter. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above), and by vaccine-type versus non-vaccine-type serotype colonies. Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, i.e. 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. Non-vaccine serotypes are defined as any other serotype. | 12 months, relative to baseline (pre-vaccination) | 
| Mean bacteriological density of vaccine- and non-vaccine-type Streptococcus pneumoniae infections, among children and adults with at least one infecting colony in the nasopharynx | The outcome is determined at the individual level, through PCR microarray analysis of nasal swab samples collected during a cross-sectional, population-representative sample survey of camp residents. Bacteriological density is estimated after PCR analysis as copies per milliliter. The analysis will be stratified by age group (0-11 months, 12-23 months, 24-59 months, 5 to 14 years, 15 to 29 years, 30 to 49 years, 50 years and above), and by vaccine-type versus non-vaccine-type serotype colonies. Vaccine-type serotypes are defined as those that the Pneumosil vaccine (Serum Institute, India) is designed to provide immunity for, i.e. 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F or 23F. Non-vaccine serotypes are defined as any other serotype. | 24 months, relative to baseline (pre-vaccination) | 
| Incidence rate of hospitalisations due to acute lower respiratory infection (ALRI) among children aged below 2 years of age | The outcome is determined at the population level, as a rate per person-time after division by the camp's estimated population of children aged below 2 years of age, updated through exhaustive census every 6 months. Hospitalisation is defined as admission of a child residing in the camp to a paediatric inpatient facility, with a final diagnosis of acute lower respiratory infection or pneumonia. The outcome is ascertained through a manual search of registers of all paediatric facilities that the camp population can realistically utilise, complemented by perusal of outpatient register records of the camp's single primary healthcare facility, to identify instances of children referred to hospitals. The diagnosis is as per clinical records. The outcome is ascertained retrospectively at baseline (vaccination campaign), and once every 6 months post-vaccination, for 24 months. However, only results after 24 months are analysed. | 24 months, relative to baseline (pre-vaccination) | 
| Rate of antibiotic prescription at outpatient care among children aged below 5 years of age | The outcome is determined at the aggregate (population) level, as a rate per person-time after division by the camp's estimated population of children aged below 5 years of age, which will also be updated through an exhaustive census every 6 months. The outcome is ascertained through consultation of the pharmacy register of the camp's single primary healthcare facility, by tallying the number of single prescriptions issued by the pharmacy to outpatients. Antibiotics are defined as per the World Health Organization's Model List of Essential Medicines. The outcome is ascertained retrospectively through record review conducted at baseline (vaccination campaign), and once every 6 months post-vaccination, for 24 months. However, only results after 24 months are analysed. | 24 months, relative to baseline (pre-vaccination) | 
| Proportion of the target population who receive the specified dosing regimen of pneumococcal conjugate vaccine during the vaccination campaign | The outcome is determined at the individual level, but will be analysed at an aggregate (population) level, with stratification by age group (6 weeks to 11 months old, 12 to 23 months old, 24 to 59 months old, 5 to 14 years old). Before the vaccination campaign, all children aged 6 weeks old to 14 years old living in the camp will be systematically identified and registered. This list will serve as the denominator for the outcome, while the numerator will be children on the list who are successfully vaccinated, as per campaign administrative records. Successful vaccination is defined as injection with two doses of Pneumosil vaccine, spaced 4 weeks apart, in children aged 6 weeks to 11 months old, and one dose of Pneumosil vaccine in children aged 1 to 14 years old. | Single time point - baseline (vaccination campaign) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pneumococcal conjugate vaccine, Humanitarian, Crisis, Forced displacement, Mass vaccination, Quasi-experimental