NIAID/DCR STUDY: INVESTIGATION OF IMMUNE AMNESIA FOLLOWING MEASLES INFECTION IN SELECT AFRICAN REGIONS

By: Katy Shaw-Saliba

Measles virus (MeV) is one of the most contagious infectious agents; thus, despite having a highly safe and effective vaccine available, sustained high vaccine coverage (>90%) is required to interrupt transmission [1]. Infection with MeV is diagnosed clinically by the presence of a characteristic fever and maculopapular rash, potentially accompanied by coryza, cough, conjunctivitis,
and small white spots in the oral mucosa known as Kolpik’s spots. Laboratory confirmation is needed using PCR to detect the MeV nucleic acid and/ or ELISA to detect anti-MeV IgM as other febrile rash illnesses have overlapping symptoms (with perhaps the exception of Kolpik’s spots). MeV can cause serious complications both in the acute phase of the infection and up to 2-3 years after the infection [2].

This prolonged effect of MeV is due to its fascinating dual impact on the immune system termed “immune amnesia.” The immune system generates a very robust response to MeV resulting in lifelong immunity to the virus. This robust immune response, however, comes at a cost. The MeV infects lymphoid cells resulting in lymphopenia. Lymphopenia is common in many infections;
however, MeV is unique in that it results in a very specific depletion of memory B cells with incomplete reconstitution of naïve B cells [3]. The depletion of memory B cells also leads to an almost complete loss of pre-existing antibodies generated in response to previous infections and/or vaccinations [4]. The loss of memory B cells and antibodies leaves children highly susceptible to other infections.

Vaccine misinformation, disruption in cold chain, and disease outbreaks such as Ebola and the COVID-19 pandemic have decreased vaccine coverage [5] and continual MeV outbreaks occur in West Africa [6]. Studies on immune amnesia have largely centered around European populations and macaque models. Given this, the NIAID/DCR Special Projects in Guinea (PREGUI) and Mali (UCRC) worked alongside NIAID/DCR members to develop a protocol to study measles immune amnesia in their local context (clinicaltrials.gov NCT06153979).

This study, Investigation of Immune Amnesia Following Measles Infection in Select African Regions or the Measles study, is an observational, longitudinal, prospective study with specific research questions aimed at enhancing the understanding of measles immune amnesia outside of Europe and animal models. The primary objective is to use a global antibody assay (MIPSA) that includes antigens to all known human viruses with the addition of malaria, typhoid, and tuberculosis antigens to see if the phenotype in con-served in this population. In addition to looking at the immune amnesia phenotype in this population, the other primary objective of the study is to determine if there is any difference in the ability of a child following MeV to respond to a controlled immune stimulus (a rabies vaccine) at an early timepoint compared to a late timepoint (using a neutralizing antibody assay).

Exploratory aims will address the number of hospital encounters in MeV-infected children compared to healthy controls, the MeV genomes circulating in West Africa (via whole genome sequencing of the virus), and the etiology of in children who present with signs and symptoms consistent with measles but test negative in the laboratory (via viral capture sequencing, VirCapSeq-VERT). Immune cells (PBMC) are being collected in Mali to investigate the cellular immune response both to MeV and the rabies vaccination. Findings from this study will be additive to the current literature and may be important when considering vaccination following MeV infection.

References:

1. Plans-Rubió, P., Are the Objectives Proposed by the WHO for Routine Measles Vaccination Coverage and Population Measles Immunity Sufficient to Achieve Measles Elimination from Europe? Vaccines (Basel), 2020. 8(2).
2. Griffin, D.E., Measles immunity and immunosuppression. Curr Opin Virol, 2021. 46: p. 9-14.
3. Petrova, V.N., et al., Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol, 2019. 4(41).
4. Mina, M.J., et al., Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science, 2019. 366(6465): p. 599-606.
5. Frenkel, L.D., 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): p. 378-385.
6. Truelove, S.A., W.J. Moss, and J. Lessler, Mitigating measles outbreaks in West Africa post-Ebola. Expert Rev Anti Infect Ther, 2015. 13(11): p. 1299-301.