Investigating immune amnesia after measles virus infection in two West African countries: A study protocol

Abstract

"Investigation of Immune Amnesia Following Measles Infection in Select African Regions" (ClinicalTrials.gov Identifier: NCT06153979) is a prospective, observational, longitudinal study being conducted in two West African countries; Guinea and Mali. Acute measles virus (MeV) infection has been shown to result in a loss of pre-existing immunity (immune amnesia). MeV-induced immune amnesia has not been studied in West Africa where continual MeV outbreaks occur. Additionally previous studies have relied on naturally occurring exposures to viruses to examine the immune systems ability to create antibodies. Thus, the overall goal of this protocol is to investigate the impact of MeV infection on pre-existing immunity to endemic pathogens in West Africa, observe the effect of a subsequent exposure to a novel pathogen (rabies vaccine), and measure the frequency of subsequent healthcare visits. A total of 256 children aged 1-15 years are being enrolled into one of two study arms: those with acute MeV infection (cases) as confirmed by laboratory testing and without (controls). Controls must be immune to MeV (have IgG). Blood samples are collected at multiple time points including screening (Day 0), at an optional visit to repeat IgM serology for inconclusive or negative Day 0 results (Day 7-10), and during follow-up visits on Day 14, Week 13, and Week 52. These blood samples will be tested to evaluate both humoral and cellular immune responses to a panel of viruses, bacteria, and parasites, including pathogens endemic to West Africa. To explore how recent MeV infection may affect the child's ability to respond to a new exposure, all participants will receive a rabies vaccine (as a controlled stimulus) at one of two timepoints post Day 0 visit. Biological samples will be collected after vaccination to assess if the rabies vaccine response differs: 1) between cases and controls, and 2) based on the time since acute MeV infection. In addition, the study team will collect information on healthcare encounters during the year-long follow-up to determine if there is a difference in the number of encounters by study group. The findings of this study will further the understanding of the MeV immune amnesia phenotype by understanding its impact on endemic pathogens and subsequent immune response following infection.

Fig 1. Study schedule.

Abbreviations: AE, adverse event; HIV, human immunodeficiency virus; Ig, immunoglobulin; MUAC, mid-upper arm circumference; NP, nasopharyngeal; OP, oropharyngeal; PCR, polymerase chain reaction. (X) = Each participant will receive only one 3-dose series of rabies vaccine according to randomization to early group (vaccination at Visits 2, 3, and 4) or late group (vaccination at Visits 8, 9, and 10). ^a EARLY rabies vaccination: Only participants randomized to EARLY rabies vaccine attend Visits 2, 3, 4. Visit 2 occurs 8 weeks after Day 0; Visit 3 occurs 7 days after Visit 2; Visit 4 occurs 21 to 28 days after Visit 2 AND at least 14 days after Visit 3. ^b LATE rabies vaccination: Only participants randomized to LATE rabies vaccine attend Visits 8, 9, 10. Visit 8 occurs 47 weeks after Day 0; Visit 9 occurs 7 days after Visit 8; Visit 10 occurs 21 to 28 days after Visit 8 AND at least 14 days after Visit 9. ^c Day 0 is defined as the day screening occurs and the first research blood sample is collected. Inclusion/exclusion criteria evaluation for enrollment will be completed when PCR and measles IgG/IgM and HIV results are available, generally by Day 14. All potential participants (or guardian/parent) will be informed of eligibility status by a designated study staff by phone, if possible, prior to the Day 14 scheduled study visit or at the Day 14 scheduled study visit. Ineligible participants may be invited to the site to discuss test results and referral for measles vaccination if serum IgG and IgM are both negative. ^d Vital signs include temperature, heart rate, and respiratory rate; may be obtained prior to rabies vaccine administration, if clinically indicated. ^e MUAC in children 12 to 59 months old. ^f HIV testing for children younger than 24 months will be performed via PCR and repeated with Rapid Diagnostic Test (RDT) at end of study to adhere to national guidelines; HIV RDT will be performed at screening for participants 24 months and older and will not be repeated at end of study. ^g HIV and measles serum IgM/IgG results must be reviewed for eligibility confirmation prior to Day 14. ^h Blood will be collected for hemoglobin test via finger and/or heel stick. Hemoglobin and urine pregnancy rapid test results must be reviewed prior to venous blood sample collection. ⁱ Females of child-bearing potential must have a negative pregnancy test prior to enrollment and each rabies vaccine administration. ^j Measles vaccination to be administered to control participants (through the study or referral to Ministry of Health vaccination program) if serum measles IgG and IgM are both negative. ^k 5 mL is the maximum volume that will be obtained at each blood draw. ^l Vitamin A will be administered at Day 0 to all participants with clinical measles per WHO guidelines: 2 oral doses of 200,000 IU given 24 hours apart. The first dose will be administered at the study site and the second will be provided to the parent to be administered 24 hours later.

Fig 2. Study schematic.

¹Research blood samples. ² Measles vaccination in controls if confirmed to have negative serum measles IgG. ³ Rabies vaccine Dose 2 is given 7 days +2 days after Dose 1, and Dose 3 is given at Day 21 to Day 28 after Dose 1 and at least 14 days after Dose 2. ⁴Healthcare utilization assessment. Color coding: Blue: visits with research blood samples. Orange: optional visit with repeat for measles serology (IgM) for inconclusive results from the Day 0 test. Purple: visit with measles vaccination in controls if confirmed to have negative measles IgG. Green: All activities and visits pertaining to the rabies vaccine. Black: visits with healthcare utilization assessment. Red: Period in which the healthcare encounters will be recorded.