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

Karine Fouth Tchos; Renée Ridzon; Mory Cherif Haidara; Djeneba Dabitao; Esther Akpa; Daouda Camara; David Vallée; Mariam Coulibaly; Sekou Camara; Jamila Aboulhab; Mahamadou Diakité; Bassirou Diarra; Samba Diarra; Ilo Dicko; Alyson Francis; Cécé Francis Kolié; Michel Koropogui; Caeul Lim; Seydou Samaké; Sally Hunsberger; Moussa Sidibé; Ray Y Chen; Issa Konate; Seydou Doumbia; Abdoul Habib Beavogui; Kathryn Shaw-Saliba

doi:10.1371/journal.pone.0314828

. 2025 Jun 26;20(6):e0314828. doi: 10.1371/journal.pone.0314828

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

Karine Fouth Tchos ¹, Renée Ridzon ¹, Mory Cherif Haidara ², Djeneba Dabitao ³, Esther Akpa ¹, Daouda Camara ², David Vallée ⁴, Mariam Coulibaly ³, Sekou Camara ², Jamila Aboulhab ¹, Mahamadou Diakité ³, Bassirou Diarra ³, Samba Diarra ³, Ilo Dicko ³, Alyson Francis ⁵, Cécé Francis Kolié ², Michel Koropogui ², Caeul Lim ⁴, Seydou Samaké ³, Sally Hunsberger ^1,^*, Moussa Sidibé ², Ray Y Chen ¹, Issa Konate ³, Seydou Doumbia ³, Abdoul Habib Beavogui ², Kathryn Shaw-Saliba ¹

Editor: Javier Antonio Benavides-Montaño⁶

¹Division of Clinical Research, NIAID/NIH, Rockville, Maryland, United States of America

²Centre National de Formation et de Recherche en Santé Rurale (CNFRSR) de Maferinyah, Conkary, Guinea

³University Clinical Research Center, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali

⁴Clinical Monitoring Research Program Directorate (CMRPD), Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America

⁵Systex, Inc, Rockville, Maryland, United States of America

⁶Universidad Nacional de Colombia Campus Palmira, COLOMBIA

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: sally.hunsberger@nih.gov

Roles

Karine Fouth Tchos: Conceptualization, Methodology, Writing – original draft, Writing – review & editing

Renée Ridzon: Conceptualization, Writing – original draft, Writing – review & editing

Mory Cherif Haidara: Conceptualization, Methodology, Writing – review & editing

Djeneba Dabitao: Conceptualization, Methodology, Writing – review & editing

Esther Akpa: Conceptualization, Methodology, Writing – review & editing

Daouda Camara: Conceptualization, Methodology, Writing – review & editing

David Vallée: Conceptualization, Writing – review & editing

Mariam Coulibaly: Writing – review & editing

Sekou Camara: Conceptualization, Methodology, Writing – review & editing

Jamila Aboulhab: Conceptualization, Writing – review & editing

Mahamadou Diakité: Conceptualization, Methodology, Writing – review & editing

Bassirou Diarra: Conceptualization, Methodology, Writing – review & editing

Samba Diarra: Writing – review & editing

Ilo Dicko: Conceptualization, Methodology, Writing – review & editing

Alyson Francis: Conceptualization, Writing – review & editing

Cécé Francis Kolié: Conceptualization, Methodology, Writing – review & editing

Michel Koropogui: Methodology, Writing – review & editing

Caeul Lim: Methodology, Writing – review & editing

Seydou Samaké: Methodology, Writing – review & editing

Sally Hunsberger: Conceptualization, Methodology, Writing – review & editing

Moussa Sidibé: Methodology, Writing – review & editing

Ray Y Chen: Conceptualization, Methodology, Writing – review & editing

Issa Konate: Conceptualization, Methodology, Writing – review & editing

Seydou Doumbia: Conceptualization, Methodology

Abdoul Habib Beavogui: Conceptualization, Methodology, Writing – review & editing

Kathryn Shaw-Saliba: Conceptualization, Methodology, Writing – original draft, Writing – review & editing

Javier Antonio Benavides-Montaño: Editor

PMCID: PMC12200839 PMID: 40569945

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.

Introduction

Measles virus (MeV) infection is a major cause of death globally for children under five years of age [1–3]. There are reports of increases in cases in many countries, including in West Africa [4,5]. The Expanded Program on Immunization in Guinea and Mali calls for two doses of measles vaccine starting at 9 months [6,7]. According to WHO/UNICEF national immunization coverage estimates for the African region in 2022, 69% of children received the first measles vaccine and 45% received the second [6]. The rates in Mali were very close to these averages, at 70% for the first dose and 44% for the second dose, but Guinea lagged farther behind, at 47% and 3%, respectively [8]. These rates are far below the 92–95% level required for herd immunity and control of community transmission of measles [9]. This is primarily because, over the past decade, West Africa has experienced measles outbreaks following large-scale public health emergencies, such as the Ebola epidemic and the COVID-19 pandemic, which have disrupted global routine childhood vaccine coverage [10–12]. Armed conflict has also disrupted routine vaccinations in many countries, resulting in a disproportionate number of cases of vaccine preventable diseases, including measles [13,14]. Finally, some vaccination campaigns may have used vaccines where appropriate storage conditions were not maintained due to a lack of available resources or equipment. Thus, the presence of global measles outbreaks underscores the importance of studies that will contribute to a better understanding of the effect of MeV infection on morbidity and mortality.

MeV infection not only directly causes morbidity but is also associated with increased susceptibility to other infections and/or increased hospitalizations [15–19]. Measles vaccination has been associated with larger reductions in morbidity and mortality than would be expected if caused by acute MeV infection alone [19–24]. While there is a strong immune response to MeV infection that confers life-long immunity to MeV there is some evidence of a loss of existing immunity to other pathogens. This phenomenon, known as “immune amnesia” [25], is associated with a loss of memory B cells and reduced antibody repertoires from previous infections and vaccinations [26,27]. MeV-induced immune amnesia has been characterized in animal studies with ferrets and rhesus macaques and has also been examined in European populations [26,28,29]. Given the current outbreaks of measles in West Africa, this study aims to determine whether measles-induced immune amnesia occurs in African regions and affects immune responses to endemic pathogens such as Mycobacteria tuberculosis, Plasmodium species, and arthropod-borne viruses (e.g., yellow fever virus or dengue). The hypothesis of this study is that acute MeV infection induces a loss of pre-existing immunity to pathogens prevalent in select African regions. Compared to those who do not have acute MeV infection, those with acute MeV infection will: 1) lose antibody diversity from previous infections and/or vaccinations compared to baseline; 2) have an altered immune response to a known exposure at different timepoints (early vs. late) post measles infection (exposure timing is controlled by using the rabies vaccine as a controlled immune stimulus) 3) have an increased incidence of illnesses or healthcare encounters in the year following acute MeV infection.

The data gathered in this study will better characterize the effect and mechanism of measles-induced immune amnesia in children. The design of this study is described.

Materials and methods

Ethical statement

National Institute of Allergy and Infectious Diseases (NIAID) is the sponsor of the study. The main protocol and each of the site-specific appendices received approval from local ethics committees and/or health authorities prior to study implementation including the University of Sciences, Techniques and Technologies Bamako Mali #2023/210/CE/USTTB -Sept 18, 2023, and Guinea CNERS # 145/CNERS/23 -Sept 8, 2023. Prior to initiation of any study procedures, all study participants had an informed consent signed by a parent or guardian, and an assent as applicable, in a language they understand.

Clinical study design

Study Overview: “Immune Amnesia Following Measles Infection in Select African Regions” (ClinicalTrials.gov Identifier: NCT06153979), is a prospective, observational, longitudinal study being conducted in West Africa to investigate the effects of MeV infection on pre-existing immunity, vaccine response, and susceptibility to subsequent illnesses. A total of 256 children are being enrolled into 1 of 2 arms: acute MeV infection (cases) or no acute MeV infection (controls). The sample size calculations are based on the primary endpoints: geometric mean RVNA titers and mean MIPSA score for the global antibody analysis and are detailed in the Statistical Aspects section. Briefly, there is 90% power to detect a standardized difference of 0.85 between cases and controls for the geometric mean RVNA titer for the groups that receive the vaccine early vs. late. There is 90% power to detect a standardized difference in the MIPSA score of 1 between cases and controls. Both of the standardized differences (0.85 and 1.00) are as large as those observed previously [26]. Acute measles is defined as signs and symptoms consistent with measles and confirmed in the laboratory using measles-specific RT-PCR on upper respiratory specimens and anti-measles IgM on blood samples. Controls are defined as an absence of signs and symptoms, negative RT-PCR, negative on anti-measles IgM, and positive on anti-measles IgG. (Controls who are otherwise eligible at screening but with a negative anti-measles IgG are vaccinated and enrolled.) Measles RNA (YouSeq RT-PCR measles, Cat no. YSL-qP-EC-Measles-100), anti-measles IgM (Abcam ELISA, Cat no. ab108751), and anti-measles IgG (Abcam ELISA, Cat no. ab108750) will be tested using the indicated commercially available kits that are verified in each laboratory. Blood samples are collected at: screening (Day 0), at an optional visit to repeat IgM serology (Day 7–10), and during follow-up visits on Day 14, Week 13, and Week 52. Plasma and, where available, PBMCs will be cryopreserved. Minimum blood volumes are collected in accordance with local IRBs. The blood samples will be used to address the primary, secondary, and exploratory objectives as outlined in Table 1. For children positive for measles, the upper respiratory sample and/or plasma from screening visit (Day 0) will be used to identify the measles genotype. In the children who test negative for measles but present with signs and symptoms consistent with measles, we will explore other viral pathogens as outlined in the exploratory objectives in Table 1.

Table 1. Study objectives and endpoints.

Objectives	Endpoints	Justification For Endpoints
Primary
To determine if MeV infection induces a loss of pre-existing immunity (immune amnesia) to endemic pathogens at Week 13 after baseline in children in select African regions.	Mean change in a panel of antibody levels over 13 weeks as measured by multiplex serological methods (e.g., Molecular Indexing of Proteins by Self-Assembly (MIPSA) with an updated VirScan library and additional libraries with endemic bacteria and parasite) and targeted ELISAs for confirmation using plasma collected at Screening (Day 0) and Week 13.	These methods detect antibodies against multiple diverse pathogens and epitopes and assess both neutralizing and non-neutralizing antibodies.
To determine the effect of MeV infection on immune response to a controlled immune stimulus (rabies vaccination) at early and late timepoints post-infection.	Geometric mean RVNA titer 5–6 weeks after the first rabies vaccine dose using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine.	These tests will measure the immune response and functionality of antibodies raised against the rabies vaccine.
	Proportion of subjects with an RVNA titer ≥ lower limit of quantification 5–6 weeks after the first rabies vaccine dose using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine.
	Proportion of subjects with rabies virus neutralizing antibodies (RVNA) titer ≥ 0.5 International Units per milliliter (IU/mL) as measured by rapid fluorescent focus inhibition test 14 days after the last PrEP regimen vaccination using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine.
Secondary
To determine if there is an increase in healthcare system encounters in the year following enrollment in children with recent MeV infection compared to those without recent MeV infection.	Mean number of non-study sick visit healthcare system encounters during the 1-year follow-up.	Visits to the healthcare system for sick visits in the year following enrollment in children with recent MeV infection will help determine the clinical impact of the immune amnesia in an objective manner.
To determine if MeV infection induces a loss of pre-existing immunity (immune amnesia) to endemic pathogens at Week 52 after baseline in children in select African regions.	Mean change in a panel of antibody levels over 52 weeks as measured by multiplex serological methods (e.g., MIPSA with an updated VirScan library and additional libraries with endemic bacteria and parasite) and targeted ELISAs for confirmation using plasma from screening (Day 0) and Week 52.	These methods detect antibodies against multiple diverse pathogens and epitopes. These represent the spectrum of both neutralizing and non-neutralizing antibodies.
Exploratory
To assess the appearance and continued production of B and T cells, especially ASCs from peripheral blood mononuclear cells (PBMCs) in circulation following MeV infection in children 1–15 years old in a subset of participants, depending on availability of collected blood samples.	Mean change in cell number and functionality from baseline (screening) to 14 days. PBMCs from screening (Day 0) and D14.	Assessing the number and functionality of the B and T cells including ASCs will give insight into the impact of MeV on B cell development and humoral immunity.
To attempt to identify the etiology of illness in children who present with signs and symptoms consistent with measles and are screened but not enrolled due to negative measles PCR and IgM.	Unbiased next generation sequencing for pathogen discovery directly from the oropharyngeal (OP)/nasopharyngeal (NP) swab and/or plasma from screening (Day 0).	This may identify other pathogens that may mimic the clinical presentation of MeV in children who have symptoms but test negative.
To identify the genotypes of MeV collected in the study.	Next generation sequencing or targeted Sanger sequencing directly from the OP/NP and/or plasma from screening (Day 0).	This will allow identification of different genotypes of MeV in the countries enrolling participants.
To characterize the phenotype of the rash and/or Koplik spots in children who present with signs and symptoms consistent with measles who test positive for measles (polymerase chain reaction [PCR] and/or IgM positive) and who test negative for measles (PCR and IgM negative).	Differences in rash patterns/presentation in children who test positive versus those who test negative for measles based on analysis of photographs.	This will allow for a comparison of rash and/or Koplik spot presentation in potential cases that end up testing positive or negative for measles in the laboratory. This will complement the exploratory objective of identifying the etiology via unbiased next general sequencing in the participants who test negative for measles. In addition, we can contribute images of measles rash on dark skinned children and Koplik spots to the medical literature.

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To explore how recent MeV infection affects the ability to respond to a new previously unencountered pathogen at two different timepoints following MeV infection, participants will receive rabies vaccine pre-exposure prophylaxis (PrEP) with Verorab inactivated rabies vaccine (Sanofi) as part of the study. PrEP is given as none of the children in the study would have previously been vaccinated or exposed to rabies. PrEP is intended to protect the recipient in case they are subsequently exposed to rabies. Previous studies have shown that children who receive a vaccine following MeV infection may have a lower antibody response to the vaccine [30]. The rabies vaccine was chosen because it is an immunogen to which most participants have not been exposed and thus can be used to measure the immune response to a newly encountered antigenic stimulus. Additionally, as rabies is estimated to cause 59,000 human deaths annually worldwide with the highest mortality in Africa [31,32], the provision of rabies PrEP is a benefit to participants in the study [33]. All children in each arm will receive rabies vaccination (3-dose series at Days 1, 7 and 28 given as PrEP), with the first dose randomized to either Week 8 or Week 47 after enrollment. WHO now recommends a 2-dose PrEP schedule [32] but we decided to use the older 3-dose schedule from the Verorab package insert (https://www.medicines.org.uk/emc/files/pil.15572.pdf) to give the acute measles cohort children the best chance of developing an immune response in the event of persisting immune amnesia. Biological samples will be collected after vaccination to assess if the immune stimulus (rabies vaccine) response differs: 1) between children with and without MeV infection, and 2) based on the timing of the receipt of the rabies vaccine. A participant who is potentially exposed to rabies during study participation will be provided rabies post exposure prophylaxis (PEP) with Verorab vaccine, with or without human rabies immune globulin, based on published recommendations [33]. The study schedule is depicted in Fig 1.

Fig 1 — 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.

The study team will collect, to the extent possible, information on healthcare encounters that take place during the year-long follow-up. This will be compared between cases and controls to determine if there is a difference in the number of encounters by study group.

The study objectives and endpoints are shown in Table 1.

Eligibility

The study inclusion and exclusion criteria are shown in Table 2. Children aged 1–15 years who are eligible after initial screening are enrolled in Group 1 of children with acute MeV infection (cases) or Group 2 of children without acute MeV infection (controls) eligible for the study and will be referred for care. An upper respiratory specimen (oropharyngeal (OP)/nasopharyngeal (NP)) for MeV PCR and plasma for measles IgM/IgG serology are collected. Plasma and PBMCs are also collected at screening for research assays. PBMCs will only be collected in Mali due to operational constraints and lack of dry ice in Guinea. Anyone suspected of having measles at the time of screening will be treated with Vitamin A 200,000 IU by mouth each day for 2 days, as recommended by the WHO [34].

Table 2. Study inclusion and exclusion criteria.

Inclusion Criteria

Exclusion Criteria

Aged 1–15 years.
Ability of the participant’s legal or culturally acceptable representative to provide informed consent.
Ability to give assent, as appropriate.
Stated willingness of parent/guardian and participant as appropriate, to comply with all stufdy procedures.
Willingness to receive rabies vaccine.
Meet the criteria for assignment to Group 1 or Group 2, as follows:
- Group 1, cases (acute MeV infection):

Clinical signs and symptoms suggestive of acute MeV infection (Koplik spots or skin rash) AND
Laboratory confirmed measles:
Upper respiratory specimen (swab) PCR for measles positive.
OR
Serum IgM for measles positive.
- Group 2, controls (no acute MeV infection):
No clinical signs and symptoms suggestive of acute MeV infection (Koplik spots or skin rash) AND
Upper respiratory specimen (swab) PCR negative for MeV AND
Serum measles IgM negative AND
Serum measles IgG positive and previously vaccinated for measles (2^nd dose will be offered if appropriate). If serum measles IgG is negative, participant must be willing to be vaccinated regardless of prior measles vaccine history to meet this criterion.

HIV infection or any other immunosuppressive condition or medications.
Pregnant or lactating.
History of prior measles or immunologic evidence of prior measles in the absence of prior measles vaccination.
Severe anemia, defined as hemoglobin less than 8 g/dL.
Any acute or chronic condition which, in the opinion of the investigator, constitutes a contraindication to participation in this study.

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Study visits according to initial protocol

A schematic depiction of the study visit timing is shown in Fig 2. During Visit 0 on Day 0, demographic, medical history, vaccination history and concomitant medication information are collected, and a physical exam is performed. Mid upper arm circumference is obtained in children ≤59 months. Due to the turnaround time for the MeV PCR and measles IgM/IgG in the laboratory, eligibility as a case or control is confirmed at Visit 1 on Day 14. Measles vaccination will be administered to controls who do not have a positive measles IgG at this visit. Once enrolled, participants will be randomized to receive 3 doses of rabies vaccine as PrEP early (doses at Weeks 8, 9, 11–12) or late (doses at Weeks 47, 48, 50–51). At Weeks 26 and 39, a healthcare questionnaire will be administered. Participants’ last visit is scheduled for Week 52. This longer follow-up period is to allow examination of antibody repertoire dynamics paired with number of healthcare encounters, as previous studies have shown that children may remain susceptible to infections for up to 1–3 years following measles infection. Windows around study visits are relatively short so that the targeted endpoints can be captured accurately. Visits that occur out of the window periods are permitted under special circumstances, to avoid missed visits. A research blood sample is collected at Days 0 (screening) and 14(pre-vaccines), and Weeks 13 (up to 6 weeks after first early rabies vaccine dose) and 52 (up to 6 weeks after first late Rabies vaccine dose, and 1 year follow up visit); prior to collection of blood, hemoglobin is checked in all participants via a fingerstick, and a urine pregnancy test is obtained in females starting at their reproductive age. Anyone found to be pregnant is withdrawn from the study. If the hemoglobin is < 8 g/dl at any follow up blood draw visit, the participant remains in the study, but a blood sample is not collected at that time.

Study sites

This study is being conducted in Guinea and Mali, which were chosen based on measles epidemiology, existing research infrastructure, and ongoing partnerships between their Ministries of Health, and in Mali, the Ministry of Higher Education, and the National Institute of Allergy and Infectious Diseases (NIAID) in the United States.

The Partnership for Clinical Research in Guinea (PREGUI) aims to conduct and implement a program of national and international, high-quality research on public health priorities in Guinea, and to build and develop sustainable research capacity. This study is implemented at two sites under PREGUI, both located within treatment centers for diseases with epidemic potential at referral hospitals in Forécariah and Mafèrinyah. These sites receive referrals from surrounding health centers, health posts and communities and are each served by a multidisciplinary team.

The University Clinical Research Center (UCRC) is located at the University of Sciences, Techniques, and Technologies of Bamako in Mali. Its mission is to promote clinical research and training at international standards in Mali and within the West Africa region. The UCRC offers competence in clinical research including clinical operations, laboratory diagnosis and exploration of immune function, data management, pharmacy and community engagement. The research team recruits participants from the Commune VI Reference Health Center and the Bakorobabougou Community Health Center, both in Bamako.

The first participant was enrolled in Guinea on 01/16/2024 and in Mali on 02/26/2024. The study is currently enrolling and the expected completion of enrolment is 05/31/2025 for both Mali and Guinea.

Amendment

After screening the first 33 potential participants with suspected measles, laboratory results confirmed measles was present in only 15 (45.5%), showing that the clinical diagnosis does not always match the validated laboratory assay results. Due to concerns that true measles cases were being missed because the IgM test was possibly conducted too early, prior to development of the IgM response but after the viremic period leading to false negative results [35–38], the protocol was amended. Thus, children highly suspected of measles based on their clinical presentation but who tested negative on both PCR and IgM at day 0 may have an optional visit between days 7–10 to retest for measles IgM [35–38]. Adding a day 7–10 re-test allows more time for the IgM response to develop. Optional photography of participants being screened as potential cases was also added to the protocol. Photographs of the rash in confirmed measles cases will be used to train study staff to improve recognition of acute MeV infection in dark skinned children and serve as an educational tool for the medical community. In screened potential cases who test measles negative, these photos will be coupled with the information gained in the exploratory aim of unbiased sequencing of other pathogens to determine the phenotype of other febrile rash illnesses that may otherwise be clinically diagnosed as measles.

Laboratory and stored specimens

The RNA is extracted from the NP/OP swabs collected in viral transport media (VTM) at screening and tested by RT-PCR for MeV. Remaining VTM samples will be stored for sequencing and genotyping of MeV. Samples from children with signs and symptoms consistent with measles but who test negative are stored and can be examined for other viruses using pathogen discovery sequencing methods. Measles IgG and IgM are measured using an enzyme linked immunoassay on plasma samples. The screening tests used in each country (hemoglobin, pregnancy, measles serology, HIV) all underwent verification prior to study start to ensure the reproducibility and accuracy of the results. Plasma collected at baseline (Visit 0), week 13 (Visit 5) and week 52 (Visit 11) will be tested at a commercial laboratory in the United States to measure antibody binding to epitopes of select viruses, bacteria and parasites using validated multiplex serological methods (e.g., Molecular Indexing of Proteins by Self-Assembly [MIPSA] technology with an updated library and additional libraries with endemic bacteria and parasites) [26,39]. PBMCs are isolated from blood specimens from Mali, stored in liquid nitrogen, and will be analyzed for antibody secreting cells (ASC). Plasma obtained following rabies vaccination will be shipped to a commercial laboratory accredited to perform Rapid Fluorescent Foci Inhibition Test (RFFIT) to ensure neutralizing antibody (RVNA) response to the rabies vaccine and to compare cases to controls and those randomized to early vaccination versus late vaccination. Samples not used for analyses will be stored and managed electronically in the local biorepositories under appropriate temperature with constant monitoring.

Safety reporting and monitoring

Safety reporting and monitoring is done according to national regulatory guidelines and International Council for Harmonisation (ICH). A clinician with appropriate expertise (Principal Investigator [PI]/Designee) will assess adverse event (AE) severity, according to the “Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events” (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) and determine the seriousness, relatedness and expectedness of the event. This may be done in coordination with the sponsor, NIAID. Per study specific standard operating procedure, only AEs related to study procedures will be followed through resolution or until the local investigator judges that the event has stabilized, and no additional follow-up is required. Safety events will be tracked and submitted to the local ethics committees according to each country’s requirements as described in the site-specific appendices. All AEs will be recorded on source documents.

AEs related to the research procedures and all serious adverse events (SAEs) will be recorded in the research database, except for Grade 1 or 2 AEs that are expected. SAEs and Unanticipated Problems will be reported to Sanofi Pasteur with coded data according to the terms of a confidential Clinical Trials Agreement.

Statistical aspects

The overall sample size of the study is 256 participants, 128 enrolled as cases and 128 as controls. The sample size accounts for a 6.5% rate of dropout from the study and participants who drop out will not be replaced. The sample size is calculated to detect a difference in the RVNA geometric mean titer between the measles cases and controls who were either vaccinated at the early time point or at the late time point). If each vaccination group (early/late) contains 128 participants with 64 cases and 64 controls, there will be 90% power to detect a standardized difference in RVNA geometric mean titer of 0.85 between cases and controls under each of the vaccination conditions. There will also be 90% power to detect an interaction between group (measles/controls) and time (early/late) if the effect size is 1.19. The interaction corresponds to showing a different response between cases and controls at early and late rabies vaccine stimulus times. There is 90% power to detect standardized mean differences of 1.00 when looking for differences in the MIPSA panel of antibody responses between cases and controls in each age group. This calculation controls for multiple comparisons. This effect size was similar to those observed in the paper by Mina et al [26].

Analysis of the rabies antibody response will be performed using multivariate linear regression on the log₁₀ titer values, including terms for case/control group, early/late vaccine, country and an interaction between group and timing of vaccine. Antibody responses to a panel of antigens will be compared between case/control groups using t-tests on change from baseline. Separate analyses will be performed for the 2 age groups (1–5 and 6–15 years). A Bonferroni correction will be used to maintain a 2-sided 0.05 error rate by adjusting for the number of antibodies in the panel. A Poisson analysis will be used to compare the number of encounters with medical providers between groups.

Control participants who become infected with measles or participants from either group who become pregnant at any time during the study will be censored at the time of infection or pregnancy. A participant who has a potential rabies exposure and receives rabies PEP during the study before s/he is scheduled (randomized) to receive rabies vaccination as PrEP will be excluded from the primary analysis of the rabies vaccine but included in the immune amnesia analysis. Participants who receive at least one dose of rabies PrEP (as randomized) will be analyzed as planned. A Statistical Analysis Plan (SAP) will be prepared for the study before analyses begin.

Study conduct, data management, operational logistics and challenges

The study leadership consists of a core team of research physicians, statisticians, laboratory research scientists, clinical research pharmacist and operational experts from the Division of Clinical Research (DCR) of NIAID and both countries. Both countries have clinical research staff and infrastructure supported by DCR. The study protocol was developed collaboratively. The country teams are responsible for submission for ethical review, continuing review reports, quality management plans, protocol deviations, and SAE reports per country regulations and as requested by NIAID. At all stages, regular teleconferences and visits are held and include study leadership, country scientific/medical laboratory, data management and clinical operations teams, and serve as a forum for information exchange on topics such as recruitment, case adjudication, visit adherence, as well as providing feedback and suggestions on study procedures. A Publication Policy has been developed to guide the drafting and review of all study-related abstracts, presentations, and manuscripts, and a Publication Committee that includes representatives from NIAID and each of the country teams will be formed. For requests for secondary use of biospecimens, the Publication Committee will be approached to approve access to biospecimens. Electronic case report forms (CRFs), core standard operating procedure (SOP) documents and manuals of operation (MOP) were developed along with site-specific documents.

The study was designed to use electronic data capture into the Clinical Data Management System (CDMS). Malian staff enter data from study-specific paper source documents. Guinean staff use direct data entry into tablets in an online mode, where the data are saved automatically to the CDMS. If the internet connection is temporarily disrupted, the data are captured and uploaded to the CDMS once service is restored. This hybrid approach allows for more flexibility across sites, reduces need for printing CRFs, and requires less transcription of data by the sites. Direct data entry also allows sites to address any queries that arise from programmed data checks at time of entry. The completed data are then reviewed by the central data management team for consistency and accuracy. Randomization is also performed electronically in the CDMS.

Specimen kits with standard barcodes are used for specimen collection. The specimens collected are stored in-country under proper conditions with constant temperature monitoring and documented in an electronic system.

A monitoring plan is used for central monitoring, to facilitate compliance with GCP, guidelines and regulations, identify key activities and specify data to be reviewed for the study. Each plan was reviewed by the study teams in Guinea and Mali and the Measles Study protocol team to ensure adherence to the protocol, laboratory, and GCP requirements. In person and virtual trainings were conducted with the study staff in each country. Refresher trainings are offered as needed.

Each country has encountered challenges with study implementation. The Guinean team is working on enhancing its ability to use electronic systems for study documents and sample management, manage a heavy workload for the available laboratory staff, and ensure participants have a good understanding of study processes. The Malian team is working on increasing the number of screened volunteers by involving more community health centers in referring suspected measles cases to the team. Also, to enhance use by community mobilizers and to sensitize community members about the study, flipbooks, a consenting tool depicting the study procedure in easily understood language with images, have been translated into Bambara, the most spoken language in Mali. Because the sites experience power losses that compromise refrigeration, all study vaccines are stored off site where a continuous power supply is assured and transported to the sites as needed. Finally, due to the waxing and waning measles cases in both countries, enrollment is taking longer than expected.

Conclusion

We have designed and launched an international observational study to investigate immune amnesia following MeV infection in Guinea and Mali, which have recurrent measles outbreaks. Despite challenges of collaborative protocol development, operationalization and need for multiple authorizations to import rabies and measles vaccines, the study was successfully initiated in 2024. This effort will increase understanding on how measles immune amnesia affects the response to a previously unexposed pathogen at different time points post-acute measles infection, characterize MeV genotypes circulating in these regions, and provide insights into other viral causes of maculopapular rash illnesses in children with dark skin. This study will add to the global understanding of measles from regions previously understudied, and where measles outbreaks continue to occur due to inconsistent access to vaccines.

Supporting information

S1 File. The Immune Amnesia Following Measles in Select African Regions clinical research protocol version 3.0 11 March 2024.

(DOCX)

pone.0314828.s001.docx^{(486.5KB, docx)}

S2 File. SPIRIT international standard checklist for the Immune Amnesia Following Measles in Select African Regions clinical research protocol.

(DOCX)

pone.0314828.s002.docx^{(53.1KB, docx)}

Acknowledgments

We thank PREGUI study team members, Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah, Centres de Santé Amélioré de Mafèrinyah, Hôpital Préfectoral de Forecariah, Community leaders in Maferyniah and Forecariah, Guinea; UCRC study team members, Centre de Santé Communautaire de Bakorobabougou, Centres de Santé de Reference Commune VI, Direction Générale de la Santé et de l’Hygiène Publique, Direction Régionale de la Santé of Bamako and Koulikoro, Community partners, Mali; Diane Griffin (deceased) and Jessica Rubens, Johns Hopkins University. We are grateful to Sanofi-Pasteur for contributions.

Data Availability

This article does not report any data and the data availability policy is not applicable.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Frenkel LD. The global burden of vaccine-preventable infectious diseases in children less than 5 years of age: Implications for COVID-19 vaccination. How can we do better?. Allergy Asthma Proc. 2021;42(5):378–85. doi: 10.2500/aap.2021.42.210065 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Vittrup DM, Laursen ACL, Malon M, Soerensen JK, Hjort J, Buus S, et al. Measles-mumps-rubella vaccine at 6 months of age, immunology, and childhood morbidity in a high-income setting: study protocol for a randomized controlled trial. Trials. 2020;21(1):1015. doi: 10.1186/s13063-020-04845-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.WHO. WHO. Measles fact sheet. 2023. Accessed 2024 February 7. https://www.who.int/en/news-room/fact-sheets/detail/measles [Google Scholar]
4.WHO. A 30-fold rise of measles cases in 2023 in the WHO European region warrants urgent action. 2023. https://www.who.int/europe/news/item/14-12-2023-a-30-fold-rise-of-measles-cases-in-2023-in-the-who-european-region-warrants-urgent-action [Google Scholar]
5.Patel MK, Goodson JL, Alexander JP Jr, Kretsinger K, Sodha SV, Steulet C, et al. Progress toward regional measles elimination–worldwide, 2000-2019. MMWR Morb Mortal Wkly Rep. 2020;69(45):1700–5. doi: 10.15585/mmwr.mm6945a6 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.WHO. African region reported cases of vaccine-preventable diseases (VPDs). 2023. https://immunizationdata.who.int/global/wiise-detail-page/vaccination-schedule-for-country_name?DISEASECODE=&TARGETPOP_GENERAL= [Google Scholar]
7.Diallo M, Dicko I, Dembélé S, Konaté B, Doumbia CO, Sanogo I, et al. Comparing vaccination coverage before and during COVID-19 pandemic in children under one year in the health district of commune V in Bamako, Mali. BMC Pediatr. 2023;23(1):599. doi: 10.1186/s12887-023-04416-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.WHO. Global health observatory data repository. 2023. https://apps.who.int/gho/data/node.main.A826 [DOI] [PubMed] [Google Scholar]
9.Griffin DE. Measles vaccine. Viral Immunol. 2018;31(2):86–95. doi: 10.1089/vim.2017.0143 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.SeyedAlinaghi S, Karimi A, Mojdeganlou H, Alilou S, Mirghaderi SP, Noori T, et al. Impact of COVID-19 pandemic on routine vaccination coverage of children and adolescents: a systematic review. Health Sci Rep. 2022;5(2):e00516. doi: 10.1002/hsr2.516 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
11.Shet A, Carr K, Danovaro-Holliday MC, Sodha SV, Prosperi C, Wunderlich J, et al. Impact of the SARS-CoV-2 pandemic on routine immunisation services: evidence of disruption and recovery from 170 countries and territories. Lancet Glob Health. 2022;10(2):e186–94. doi: 10.1016/S2214-109X(21)00512-X [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Truelove SA, Moss WJ, Lessler J. Mitigating measles outbreaks in West Africa post-Ebola. Expert Rev Anti Infect Ther. 2015;13(11):1299–301. [DOI] [PubMed] [Google Scholar]
13.Grundy J, Biggs B-A. The impact of conflict on immunisation coverage in 16 countries. Int J Health Policy Manag. 2019;8(4):211–21. doi: 10.15171/ijhpm.2018.127 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Jawad M, Hone T, Vamos EP, Cetorelli V, Millett C. Implications of armed conflict for maternal and child health: a regression analysis of data from 181 countries for 2000-2019. PLoS Med. 2021;18(9):e1003810. doi: 10.1371/journal.pmed.1003810 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Behrens L, Cherry JD, Heininger U. The susceptibility to other infectious diseases following measles during a three year observation period in Switzerland. Pediatr Infect Dis J. 2020;39(6):478–82. [DOI] [PubMed] [Google Scholar]
16.Bühl D, Staudacher O, Santibanez S, Rossi R, Girschick H, Stephan V, et al. Specifically increased rate of infections in children post measles in a high resource setting. Front Pediatr. 2022;10:896086. doi: 10.3389/fped.2022.896086 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Gadroen K, Dodd CN, Masclee GMC, de Ridder MAJ, Weibel D, Mina MJ, et al. Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK. BMJ Open. 2018;8(11):e021465. doi: 10.1136/bmjopen-2017-021465 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Le NTH, Ho NT, Grenfell B, Baker S, Geskus RB. Biphasic pattern in the effect of severe measles infection; the difference between additive and multiplicative scale. BMC Infect Dis. 2021;21(1):1249. doi: 10.1186/s12879-021-06930-x [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Sato R, Haraguchi M. Effect of measles prevalence and vaccination coverage on other disease burden: evidence of measles immune amnesia in 46 African countries. Hum Vaccin Immunother. 2021;17(12):5361–6. doi: 10.1080/21645515.2021.2013078 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Aaby P, Bhuiya A, Nahar L, Knudsen K, de Francisco A, Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol. 2003;32(1):106–16. doi: 10.1093/ije/dyg005 [DOI] [PubMed] [Google Scholar]
21.Aaby P, et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ. 1995;311(7003):481–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K, Christensen H, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016;355:i5170. doi: 10.1136/bmj.i5170 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Mina MJ. Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits. J Infect. 2017;74 Suppl 1:S10–7. doi: 10.1016/S0163-4453(17)30185-8 [DOI] [PubMed] [Google Scholar]
24.Sørup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA. 2014;311(8):826–35. doi: 10.1001/jama.2014.470 [DOI] [PubMed] [Google Scholar]
25.Griffin DE. Measles immunity and immunosuppression. Curr Opin Virol. 2021;46:9–14. doi: 10.1016/j.coviro.2020.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science. 2019;366(6465):599–606. doi: 10.1126/science.aay6485 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, et al. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol. 2019;4(41):eaay6125. doi: 10.1126/sciimmunol.aay6125 [DOI] [PubMed] [Google Scholar]
28.Laksono BM, de Vries RD, Verburgh RJ, Visser EG, de Jong A, Fraaij PLA, et al. Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands. Nat Commun. 2018;9(1):4944. doi: 10.1038/s41467-018-07515-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Cox RM, Wolf JD, Lieberman NA, Lieber CM, Kang H-J, Sticher ZM, et al. Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets. Nat Commun. 2024;15(1):1189. doi: 10.1038/s41467-024-45418-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Ashbaugh HR, Cherry JD, Hoff NA, Doshi RH, Mukadi P, Higgins SG, et al. Reported history of measles and long-term impact on tetanus antibody detected in children 9-59 months of age and receiving 3 doses of tetanus vaccine in the democratic republic of the congo. Pediatr Infect Dis J. 2023;42(4):338–45. doi: 10.1097/INF.0000000000003840 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.WHO. Control of neglected tropical diseases: rabies, epidemiology and burden of disease: global burden of dog-transmitted human rabies. Accessed 2024 February 7. https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/epidemiology-and-burden [Google Scholar]
32.WHO. WHO expert consultation on rabies: WHO-TRS-1012. 2018. 2024 February 7. https://www.who.int/publications/i/item/WHO-TRS-1012 [Google Scholar]
33.CDC. Rabies postexposure prophylaxis (PEP). 2022. https://www.cdc.gov/rabies/medical_care/index.html#:~:text=Postexposure%20prophylaxis%20(PEP)%20consists%20of,3%2C%207%2C%20and%2014 [Google Scholar]
34.WHO. Measles. 2023. https://www.who.int/news-room/fact-sheets/detail/measles. [Google Scholar]
35.Woo GKS, Wong AH, Lee WY, Lau CS, Cheng PKC, Leung PCK, et al. Comparison of laboratory diagnostic methods for measles infection and identification of measles virus genotypes in Hong Kong. J Med Virol. 2010;82(10):1773–81. doi: 10.1002/jmv.21888 [DOI] [PubMed] [Google Scholar]
36.WHO. Chapter 3. Clinical specimens for the laboratory confirmation and molecular epidemiology of measles, rubella, and CRS. In: Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome. [Google Scholar]
37.CDC. Pattern of wild test results among patients with wild measles infection, by day from rash onset and type of sampling method used. WHO Measdles and Rubella laboratory network. 2008.
38.WHO measles and rubella laboratory network: 2007 meeting on use of alternative sampling techniques for surveillance. 2008. p. 225–232 [PubMed] [Google Scholar]
39.Credle JJ, Gunn J, Sangkhapreecha P, Monaco DR, Zheng XA, Tsai H-J, et al. Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries. Nat Biomed Eng. 2022;6(8):992–1003. doi: 10.1038/s41551-022-00925-y [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. 2025 Jun 26;20(6):e0314828. doi: 10.1371/journal.pone.0314828.r001

Author response to Decision Letter 0

22 Nov 2024

PLoS One. doi: 10.1371/journal.pone.0314828.r002

Decision Letter 0

Pierre Roques

20 Dec 2024

Dear Dr. Fouth Tchos,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: No

**********

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Reviewer #1: Yes

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Reviewer #1: No

**********

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Reviewer #1: This is a study protocol that will be useful in research, but important points need to be clarified, such as the choice of study cohort, key questions about the vaccination status of the children in the cohort, and the fact that the latest measles vaccination coverage figures are not very high, which should be taken into account.

It should be made clear why the rabies vaccine was used and not another vaccine. The key points are not easy to find in the text, as the sentences are a little too long and therefore difficult to understand. This protocol needs to be read by a native English speaker.

**********

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pone.0314828.s003.docx^{(20.3KB, docx)}

PLoS One. 2025 Jun 26;20(6):e0314828. doi: 10.1371/journal.pone.0314828.r003

Author response to Decision Letter 1

11 Feb 2025

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

This manuscript presents an important study that could significantly contribute to our understanding of immune amnesia associated with measles infection. Addressing the points mentioned above will enhance clarity, transparency, and rigor, ultimately supporting the validity of the research findings.

I'll be looking at clarity, structure, grammar and relevance of content. This article needs to be read by a native English speaker.

This manuscript was read by all of the authors which includes five native English speakers and all of the non-native English-speaking authors are proficient in English. We would like to suggest to the Editor and reviewer to refrain from using the term “native English speaker” as it makes unsupported assumptions on the authors’ origins and capacity. We appreciate the comment to improve the clarity and grammar of the manuscript and have done so in this resubmission.

Title:

The title is informative and precise. However, it could benefit from simplification, for example:

- “Study of immune amnesia following measles virus infection in West Africa”.

Response: Thank you for this consideration. The title is derived from the protocol title and what is captured in ClinicalTrials.gov Identifier: NCT06153979. We would like to propose therefore keeping the full title. The short title has been updated to reflect the suggestion from the reviewer.

Abstract:

What is the working hypothesis?

Response: The working hypothesis is that acute MeV infection induces a loss of pre-existing immunity to pathogens prevalent in select African regions. Compared to those who do not have acute MeV infection, acute MeV infection may result in 1) A loss of antibody diversity from previous infections and/or vaccinations compared to screening; 2) Altered immune response to a controlled immune stimulus (rabies vaccination) given at two different timepoints; 3) Increased incidence of illnesses or healthcare encounters in the year following acute MeV infection. The abstract has been reworked to more clearly highlight the objectives of the study.

Line 16: “Investigation of Immune Amnesia Following Measles Infection in Select African Regions.”

Correction: Make sure this sentence aligns with the article title.

Response: Line 16 aligns with the article title and reflects the protocol title as identified in ClinicalTrials.gov Identifier: NCT06153979.

Line17-18: “a prospective, observational, longitudinal study being conducted in two West African countries, Guinea, and Mali.”

Correction: Delete the comma after “Guinea”.

Response: This has been updated.

Material and methods

Line 86: Although you mention enrolling 256 children, further justification of this sample size in terms of statistical power and expected effect sizes would strengthen the manuscript. Please explain the basis for this number and if any preliminary data guided this decision.

The manuscript includes the detailed explanation for the sample size justification in the Statistical Aspect section (clean version line 295). However, for clarity and in response to the feedback, the following has been added to the material and methods (clean version line 92): “The sample size calculations are based on the primary endpoints: geometric mean RVNA titers and mean MIPSA score for the global antibody analysis and are detailed in the Statistical Aspects section. Briefly, there is 90% power to detect a standardized difference of 0.85 between cases and controls for the geometric mean RVNA titer for the groups that receive the vaccine early vs. late. There is 90% power to detect a standardized difference in the MIPSA score of 1 between cases and controls. Both of the standardized differences (0.85 and 1.00) are as large those observed previously 1.” The sample size calculations were based on the previous study that identified the loss of pre-existing antibodies (immune amnesia), which is properly referenced throughout the manuscript: Mina, M.J., et al., Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science, 2019. 366(6465): p. 599-606.

Line 87: “Acute MeV is confirmed by RT-PCR testing on upper respiratory specimens or IgM detection on blood samples at screening.”

Correction: Clarify “screening” by specifying the time of evaluation.

Response: We have added Day 0 (D0) to “screening” here and throughout the manuscript for clarity.

Please cite the reference of the method you will use. Please indicate which kit to use and the supplier.

Response: The following has been added (clean version line 103): “Measles RNA (YouSeq RT-PCR measles, Cat no. YSL-qP-EC-Measles-100), anti-measles IgM (Abcam ELISA, Cat no. ab108751), and anti-measles IgG (Abcam ELISA, Cat no. ab108750)” will be tested using the indicated commercially available kits that are verified in each laboratory.”

Line 88-89: “Blood samples are collected at multiple time points at 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.”

Comment: Clarify the purpose of the blood drive and what will be measured.

Response: We have clarified both in the text in the methods and Table 1 what objectives will be addressed with the blood that is collected.

The following information has been added to the text (clean version line 107): “Plasma and, where available, PBMCs will be cryopreserved. Minimum blood volumes are collected in accordance with local IRBs. The blood samples will be used to address the primary, secondary, and exploratory objectives as outlined in Table 1. For children positive for measles, the upper respiratory sample and/or plasma from screening visit (Day 0) will be used to identify the measles genotype in the children who test negative for measles but present with signs and symptoms consistent with measles, we will explore other viral pathogens as outlined in the exploratory objectives in Table 1.as outlined in the exploratory objectives in Table 1.”

Updated Table 1:

OBJECTIVES ENDPOINTS JUSTIFICATION FOR ENDPOINTS

Primary

To determine if MeV infection induces a loss of pre-existing immunity (immune amnesia) to endemic pathogens at Week 13 after baseline in children in select African regions. Mean change in a panel of antibody levels over 13 weeks as measured by multiplex serological methods (e.g., Molecular Indexing of Proteins by Self-Assembly (MIPSA) with an updated VirScan library and additional libraries with endemic bacteria and parasite) and targeted ELISAs for confirmation using plasma collected at Screening (D0) and Week 13. These methods detect antibodies against multiple diverse pathogens and epitopes and assess both neutralizing and non-neutralizing antibodies.

To determine the effect of MeV infection on immune response to a controlled immune stimulus (rabies vaccination) at early and late timepoints post-infection.

Geometric mean RVNA titer 5-6 weeks after the first rabies vaccine dose using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine. These tests will measure the immune response and functionality of antibodies raised against the rabies vaccine.

Proportion of subjects with an RVNA titer ≥ lower limit of quantification 5-6 weeks after the first rabies vaccine dose using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine.

Proportion of subjects with rabies virus neutralizing antibodies (RVNA) titer ≥ 0.5 International Units per milliliter (IU/mL) as measured by rapid fluorescent focus inhibition test 14 days after the last PrEP regimen vaccination using plasma from D14 (randomization) as pre-vaccine and at either Week 13 (early randomization) or Week 52 (late randomization) as post-vaccine.

Secondary

To determine if there is an increase in healthcare system encounters in the year following enrollment in children with recent MeV infection compared to those without recent MeV infection. Mean number of non-study sick visit healthcare system encounters during the 1-year follow-up. Visits to the healthcare system for sick visits in the year following enrollment in children with recent MeV infection will help determine the clinical impact of the immune amnesia in an objective manner.

To determine if MeV infection induces a loss of pre-existing immunity (immune amnesia) to endemic pathogens at Week 52 after baseline in children in select African regions. Mean change in a panel of antibody levels over 52 weeks as measured by multiplex serological methods (e.g., MIPSA with an updated VirScan library and additional libraries with endemic bacteria and parasite) and targeted ELISAs for confirmation using plasma from screening (D0) and Week 52. These methods detect antibodies against multiple diverse pathogens and epitopes. These represent the spectrum of both neutralizing and non-neutralizing antibodies.

Exploratory

To assess the appearance and continued production of B and T cells, especially ASCs from peripheral blood mononuclear cells (PBMCs) in circulation following MeV infection in children 1-15 years old in a subset of participants, depending on availability of collected blood samples. Mean change in cell number and functionality from baseline (screening) to 14 days. PBMCs from screening (D0) and D14.

Assessing the number and functionality of the B and T cells including ASCs will give insight into the impact of MeV on B cell development and humoral immunity.

To attempt to identify the etiology of illness in children who present with signs and symptoms consistent with measles and are screened but not enrolled due to negative measles PCR and IgM. Unbiased next generation sequencing for pathogen discovery directly from the oropharyngeal (OP)/nasopharyngeal (NP) swab and/or plasma from screening (D0). This may identify other pathogens that may mimic the clinical presentation of MeV in children who have symptoms but test negative.

To identify the genotypes of MeV collected in the study. Next generation sequencing or targeted Sanger sequencing directly from the OP/NP and/or plasma from screening (D0). This will allow identification of different genotypes of MeV in the countries enrolling participants.

To characterize the phenotype of the rash and/or Koplik spots in children who present with signs and symptoms consistent with measles who test positive for measles (polymerase chain reaction [PCR] and/or IgM positive) and who test negative for measles (PCR and IgM negative).

Differences in rash patterns/presentation in children who test positive versus those who test negative for measles based on analysis of photographs. This will allow for a comparison of rash and/or Koplik spot presentation in potential cases that end up testing positive or negative for measles in the laboratory. This will complement the exploratory objective of identifying the etiology via unbiased next general sequencing in the participants who test negative for measles. In addition, we can contribute images of measles rash on dark skinned children and Koplik spots to the medical literature.

I didn't understand the reason for week 52, could I have an explanation?

Response: Week 52 was chosen for a few reasons. First, participants are randomized to receive rabies at an early timepoint (8 weeks) or a late timepoint (47 weeks) following their measles infection. In consultation with Sanofi, the peak anti-rabies antibody production occurs at 5-6 weeks after the first dose of the vaccine, which resulted in 52 weeks. Second, the Mina, M.J., et al., Science, 2019. 366(6465): p. 599-606 paper looking at the global loss of pre-existing antibodies looked at the change in antibody binding profile at a median of 10 weeks post-infection. The primary objective will look at 13 weeks at this study. We also wanted to follow the children up to one year to examine a longer follow-up period and potential return of the antibody repertoire paired with the number of healthcare encounters. Previous studies have shown that children remain susceptible to other infections up to 1-3 years following infection [Behrens L, et al. Pediatr Infect Dis J 2020; 39(6): 478-82]. We have clarified this in the study visits section (clean version line 198)

Suggestion: Break down this sentence for greater clarity.

Response: The sentence has been changed from “Blood samples are collected at multiple time points at 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.”

“Blood samples are collected at: screening (Day 0), at an optional visit to repeat IgM serology (Day 7-10), and during follow-up visits on Day 14, Week 13, and Week 52.”

Line 90-93: “These blood samples will be tested to evaluate both humoral and cellular immune responses to endemic pathogens to measure variations in antibody diversity and antibody secreting cells (ASCs).”

Correction: Make sure the term “humoral” is understood in context.?

Response: This sentence has been removed and instead replaced by the following to clarify the intended use of plasma and PMBCS samples obtained from blood collection:

“For children positive for measles, the upper respiratory sample and/or plasma from screening visit (Day 0) will be used to identify the measles genotype In the children who test negative for measles but present with signs and symptoms consistent with measles, we will explore other viral pathogens as outlined in the exploratory objectives in Table 1.”

The objectives in Table 1 have also been updated accordingly.

You based your assessment of loss of immunity in children with measles on the fact of acute infection. Have you taken into account whether or not they have received one or 2 doses of measles vaccine? Because I think the length of time, they've been vaccinated can influence the immune response.

Response: Thank you for this consideration. The reviewer is correct in that we based our assessment on the loss of immunity in children with acute measles infection, regardless of their vaccine history. We do not think the measles vaccine regimen will have a measurable effect in our assessment of immunity loss, but we are collecting necessary data to examine this and can incorporate this into the analysis. As part of the case report forms and discussion with the parents, we are collecting measles vaccination history as reported by the parents and/or including information from the child’s vaccination record. The vaccination record is standard in Guinea and Mali. Both from the reported history and from the number of doses (1 or 2) are recorded in the case report form. Regardless of the vaccination timing and number of doses, children both in the cases and controls are also tested for anti-measles IgG at screening (D0).

Line 94-96: “To explore how recent MeV infection may affect the child’s ability to respond to a controlled immune stimulus, all participants will receive rabies vaccine pre-exposure prophylaxis (PrEP) using Verorab inactivated rabies vaccine.”

Comment: The use of “pre-exposure prophylaxis” could be further explained for readers less familiar with the term.

Response: PrEP is a common term for giving a vaccine or drug prior to exposure. We have further clarified by adding in clean version line 118: “PrEP is given as none of the children in the study would have previously been vaccinated or exposed to rabies. PrEP is intended to protect the recipient in case they are subsequently exposed to rabies.”

Figure 2: I didn't understand the color differences. Please be more explicit.

Response: Thank you for this comment. The following information has been added to the legend:

Blue: visits with research blood samples

Orange: optional visit with repeat for measles serology (IgM) for inconclusive results from the D0 test

Purple: visit with measles vaccination in controls if confirmed to have negative measles IgG

Green: All activities and visits pertaining to the rabies v

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PLoS One. doi: 10.1371/journal.pone.0314828.r004

Decision Letter 1

Javier Antonio Benavides-Montaño

25 Apr 2025

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

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PLoS One. doi: 10.1371/journal.pone.0314828.r005

Acceptance letter

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Supplementary Materials

S1 File. The Immune Amnesia Following Measles in Select African Regions clinical research protocol version 3.0 11 March 2024.

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S2 File. SPIRIT international standard checklist for the Immune Amnesia Following Measles in Select African Regions clinical research protocol.

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[pone.0314828.ref001] 1.Frenkel LD. The global burden of vaccine-preventable infectious diseases in children less than 5 years of age: Implications for COVID-19 vaccination. How can we do better?. Allergy Asthma Proc. 2021;42(5):378–85. doi: 10.2500/aap.2021.42.210065 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref002] 2.Vittrup DM, Laursen ACL, Malon M, Soerensen JK, Hjort J, Buus S, et al. Measles-mumps-rubella vaccine at 6 months of age, immunology, and childhood morbidity in a high-income setting: study protocol for a randomized controlled trial. Trials. 2020;21(1):1015. doi: 10.1186/s13063-020-04845-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref003] 3.WHO. WHO. Measles fact sheet. 2023. Accessed 2024 February 7. https://www.who.int/en/news-room/fact-sheets/detail/measles [Google Scholar]

[pone.0314828.ref004] 4.WHO. A 30-fold rise of measles cases in 2023 in the WHO European region warrants urgent action. 2023. https://www.who.int/europe/news/item/14-12-2023-a-30-fold-rise-of-measles-cases-in-2023-in-the-who-european-region-warrants-urgent-action [Google Scholar]

[pone.0314828.ref005] 5.Patel MK, Goodson JL, Alexander JP Jr, Kretsinger K, Sodha SV, Steulet C, et al. Progress toward regional measles elimination–worldwide, 2000-2019. MMWR Morb Mortal Wkly Rep. 2020;69(45):1700–5. doi: 10.15585/mmwr.mm6945a6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref006] 6.WHO. African region reported cases of vaccine-preventable diseases (VPDs). 2023. https://immunizationdata.who.int/global/wiise-detail-page/vaccination-schedule-for-country_name?DISEASECODE=&TARGETPOP_GENERAL= [Google Scholar]

[pone.0314828.ref007] 7.Diallo M, Dicko I, Dembélé S, Konaté B, Doumbia CO, Sanogo I, et al. Comparing vaccination coverage before and during COVID-19 pandemic in children under one year in the health district of commune V in Bamako, Mali. BMC Pediatr. 2023;23(1):599. doi: 10.1186/s12887-023-04416-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref008] 8.WHO. Global health observatory data repository. 2023. https://apps.who.int/gho/data/node.main.A826 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref009] 9.Griffin DE. Measles vaccine. Viral Immunol. 2018;31(2):86–95. doi: 10.1089/vim.2017.0143 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref010] 10.SeyedAlinaghi S, Karimi A, Mojdeganlou H, Alilou S, Mirghaderi SP, Noori T, et al. Impact of COVID-19 pandemic on routine vaccination coverage of children and adolescents: a systematic review. Health Sci Rep. 2022;5(2):e00516. doi: 10.1002/hsr2.516 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]

[pone.0314828.ref011] 11.Shet A, Carr K, Danovaro-Holliday MC, Sodha SV, Prosperi C, Wunderlich J, et al. Impact of the SARS-CoV-2 pandemic on routine immunisation services: evidence of disruption and recovery from 170 countries and territories. Lancet Glob Health. 2022;10(2):e186–94. doi: 10.1016/S2214-109X(21)00512-X [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref012] 12.Truelove SA, Moss WJ, Lessler J. Mitigating measles outbreaks in West Africa post-Ebola. Expert Rev Anti Infect Ther. 2015;13(11):1299–301. [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref013] 13.Grundy J, Biggs B-A. The impact of conflict on immunisation coverage in 16 countries. Int J Health Policy Manag. 2019;8(4):211–21. doi: 10.15171/ijhpm.2018.127 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref014] 14.Jawad M, Hone T, Vamos EP, Cetorelli V, Millett C. Implications of armed conflict for maternal and child health: a regression analysis of data from 181 countries for 2000-2019. PLoS Med. 2021;18(9):e1003810. doi: 10.1371/journal.pmed.1003810 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref015] 15.Behrens L, Cherry JD, Heininger U. The susceptibility to other infectious diseases following measles during a three year observation period in Switzerland. Pediatr Infect Dis J. 2020;39(6):478–82. [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref016] 16.Bühl D, Staudacher O, Santibanez S, Rossi R, Girschick H, Stephan V, et al. Specifically increased rate of infections in children post measles in a high resource setting. Front Pediatr. 2022;10:896086. doi: 10.3389/fped.2022.896086 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref017] 17.Gadroen K, Dodd CN, Masclee GMC, de Ridder MAJ, Weibel D, Mina MJ, et al. Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK. BMJ Open. 2018;8(11):e021465. doi: 10.1136/bmjopen-2017-021465 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref018] 18.Le NTH, Ho NT, Grenfell B, Baker S, Geskus RB. Biphasic pattern in the effect of severe measles infection; the difference between additive and multiplicative scale. BMC Infect Dis. 2021;21(1):1249. doi: 10.1186/s12879-021-06930-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref019] 19.Sato R, Haraguchi M. Effect of measles prevalence and vaccination coverage on other disease burden: evidence of measles immune amnesia in 46 African countries. Hum Vaccin Immunother. 2021;17(12):5361–6. doi: 10.1080/21645515.2021.2013078 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref020] 20.Aaby P, Bhuiya A, Nahar L, Knudsen K, de Francisco A, Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol. 2003;32(1):106–16. doi: 10.1093/ije/dyg005 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref021] 21.Aaby P, et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ. 1995;311(7003):481–5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref022] 22.Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K, Christensen H, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016;355:i5170. doi: 10.1136/bmj.i5170 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref023] 23.Mina MJ. Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits. J Infect. 2017;74 Suppl 1:S10–7. doi: 10.1016/S0163-4453(17)30185-8 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref024] 24.Sørup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA. 2014;311(8):826–35. doi: 10.1001/jama.2014.470 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref025] 25.Griffin DE. Measles immunity and immunosuppression. Curr Opin Virol. 2021;46:9–14. doi: 10.1016/j.coviro.2020.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref026] 26.Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science. 2019;366(6465):599–606. doi: 10.1126/science.aay6485 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref027] 27.Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, et al. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol. 2019;4(41):eaay6125. doi: 10.1126/sciimmunol.aay6125 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref028] 28.Laksono BM, de Vries RD, Verburgh RJ, Visser EG, de Jong A, Fraaij PLA, et al. Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands. Nat Commun. 2018;9(1):4944. doi: 10.1038/s41467-018-07515-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref029] 29.Cox RM, Wolf JD, Lieberman NA, Lieber CM, Kang H-J, Sticher ZM, et al. Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets. Nat Commun. 2024;15(1):1189. doi: 10.1038/s41467-024-45418-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref030] 30.Ashbaugh HR, Cherry JD, Hoff NA, Doshi RH, Mukadi P, Higgins SG, et al. Reported history of measles and long-term impact on tetanus antibody detected in children 9-59 months of age and receiving 3 doses of tetanus vaccine in the democratic republic of the congo. Pediatr Infect Dis J. 2023;42(4):338–45. doi: 10.1097/INF.0000000000003840 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0314828.ref031] 31.WHO. Control of neglected tropical diseases: rabies, epidemiology and burden of disease: global burden of dog-transmitted human rabies. Accessed 2024 February 7. https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/epidemiology-and-burden [Google Scholar]

[pone.0314828.ref032] 32.WHO. WHO expert consultation on rabies: WHO-TRS-1012. 2018. 2024 February 7. https://www.who.int/publications/i/item/WHO-TRS-1012 [Google Scholar]

[pone.0314828.ref033] 33.CDC. Rabies postexposure prophylaxis (PEP). 2022. https://www.cdc.gov/rabies/medical_care/index.html#:~:text=Postexposure%20prophylaxis%20(PEP)%20consists%20of,3%2C%207%2C%20and%2014 [Google Scholar]

[pone.0314828.ref034] 34.WHO. Measles. 2023. https://www.who.int/news-room/fact-sheets/detail/measles. [Google Scholar]

[pone.0314828.ref035] 35.Woo GKS, Wong AH, Lee WY, Lau CS, Cheng PKC, Leung PCK, et al. Comparison of laboratory diagnostic methods for measles infection and identification of measles virus genotypes in Hong Kong. J Med Virol. 2010;82(10):1773–81. doi: 10.1002/jmv.21888 [DOI] [PubMed] [Google Scholar]

[pone.0314828.ref036] 36.WHO. Chapter 3. Clinical specimens for the laboratory confirmation and molecular epidemiology of measles, rubella, and CRS. In: Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome. [Google Scholar]

[pone.0314828.ref037] 37.CDC. Pattern of wild test results among patients with wild measles infection, by day from rash onset and type of sampling method used. WHO Measdles and Rubella laboratory network. 2008.

[pone.0314828.ref038] 38.WHO measles and rubella laboratory network: 2007 meeting on use of alternative sampling techniques for surveillance. 2008. p. 225–232 [PubMed] [Google Scholar]

[pone.0314828.ref039] 39.Credle JJ, Gunn J, Sangkhapreecha P, Monaco DR, Zheng XA, Tsai H-J, et al. Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries. Nat Biomed Eng. 2022;6(8):992–1003. doi: 10.1038/s41551-022-00925-y [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

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

Karine Fouth Tchos

Renée Ridzon

Mory Cherif Haidara

Djeneba Dabitao

Esther Akpa

Daouda Camara

David Vallée

Mariam Coulibaly

Sekou Camara

Jamila Aboulhab

Mahamadou Diakité

Bassirou Diarra

Samba Diarra

Ilo Dicko

Alyson Francis

Cécé Francis Kolié

Michel Koropogui

Caeul Lim

Seydou Samaké

Sally Hunsberger

Moussa Sidibé

Ray Y Chen

Issa Konate

Seydou Doumbia

Abdoul Habib Beavogui

Kathryn Shaw-Saliba

Roles

Abstract

Introduction

Materials and methods

Ethical statement

Clinical study design

Table 1. Study objectives and endpoints.

Fig 1. Study schedule.

Eligibility

Table 2. Study inclusion and exclusion criteria.

Study visits according to initial protocol

Fig 2. Study schematic.

Study sites

Amendment

Laboratory and stored specimens

Safety reporting and monitoring

Statistical aspects

Study conduct, data management, operational logistics and challenges

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Pierre Roques

Roles

Author response to Decision Letter 1

Decision Letter 1

Javier Antonio Benavides-Montaño

Roles

Acceptance letter

Javier Antonio Benavides-Montaño

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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