By Stan Deresinski, MD, FACP

Clinical Professor of Medicine, Stanford University

SYNOPSIS: A patient without apparent immunodeficiency experienced a late relapse of Ebola virus disease with subsequent transmission causing 91 secondary cases. Such late relapse raises concerns regarding control of this disease.

SOURCE: Mbala-Kingebeni P, Pratt C, Mutafali-Ruffin M, et al. Ebola virus transmission initiated by relapse of systemic Ebola virus disease. N Engl J Med 2021;384:1240-1247.

A 25-year-old man in the Democratic Republic of Congo presented with Ebola virus disease on June 15, 2019, despite having been vaccinated against this infection six months previously. Infection was confirmed by a positive serum polymerase chain reaction (PCR) test. He was treated with an experimental monoclonal antibody preparation and subsequently discharged from the hospital after two consecutive negative PCR tests. A semen sample PCR was negative two months after presentation.  

The patient had symptom recurrence beginning on Nov. 25, 2019, 149 days after he was discharged and eventually reached the Ebola treatment unit at which he had received his previous care. Human immunodeficiency virus testing was negative, but Ebola virus ribonucleic acid (RNA) was detected repeatedly in serum, and he developed multiorgan system failure and died. Ebola PCR on postmortem saliva was positive. Genomic investigation indicated virtual identity of the virus responsible for this episode and that in the initial episode, demonstrating that the infection represented a relapse. Contact tracing investigation, confirmed by genomic analysis, identified subsequent transmission from the relapse episode to 91 cases over the subsequent four months.

COMMENTARY

Persistent Ebola virus infection has been identified previously, with persistence of virus in semen for months and with evidence of sexual transmission after recovery from the acute infection. In addition, rare cases of recrudescent symptomatic infection also have been reported, but these have not been associated with further transmission of the virus. In this case, there was complete clinical recovery from the initial case and apparent confirmed viral clearance. Nonetheless, the viral infection relapsed, not only causing the patient’s death, but leading to a large number of secondary cases.

Look-back examination found that, despite receipt of an Ebola vaccine, the patient had no detectable antibody against the virus at the time of initial presentation, although testing of a day-14 sample demonstrated that he had successfully seroconverted. Antibody was again detected eight days after the onset of his relapsed infection. The lack of antibody after vaccination has previously been known to occur in a small proportion of cases. The occurrence in this case after receipt of a therapeutic monoclonal antibody raised the question of immune escape, but the antibody retained its neutralizing activity against the virus recovered during the second episode. Finally, immunological evaluation of the patient, including whole exome sequencing, failed to identify evidence for an immune deficit.

The authors noted that two other patients, in addition to the one described, who are known to have relapsed after an acute Ebola virus infection, had received antibody-based treatment. They pointed out that administration of convalescent plasma also has been associated with cases of relapse of Argentinian hemorrhagic fever. The underlying reasons for such occurrences remain obscure, but they may raise questions regarding the use of therapeutic monoclonals in other viral infections, such as COVID-19.