Life-Threatening Infections Due to Live-Attenuated Vaccines: Early Manifestations of Inborn Errors of Immunity

Abstract

Live-attenuated vaccines (LAVs) can protect humans against 12 viral and three bacterial diseases. By definition, any clinical infection caused by a LAV that is sufficiently severe to require medical intervention attests to an inherited or acquired immunodeficiency that must be diagnosed or identified. Self-healing infections can also result from milder forms of immunodeficiency. We review here the inherited forms of immunodeficiency underlying severe infections of LAVs. Inborn errors of immunity (IEIs) underlying bacille Calmette-Guérin (BCG), oral poliovirus (OPV), vaccine measles virus (vMeV), and oral rotavirus vaccine (ORV) disease have been described from 1951, 1963, 1966, and 2009 onward, respectively. For each of these four LAVs, the underlying IEIs show immunological homogeneity despite genetic heterogeneity. Specifically, BCG disease is due to inborn errors of IFN-γ immunity, OPV disease to inborn errors of B cell immunity, vMeV disease to inborn errors of IFN-α/β and IFN-λ immunity, and ORV disease to adaptive immunity. Severe reactions to the other 11 LAVs have been described yet remain Bidiopathic,^in the absence of known underlying inherited or acquired immunodeficiencies, and are warranted to be the focus of research efforts. The study of IEIs underlying life-threatening LAV infections is clinically important for the affected patients and their families, as well as immunologically, for the study of the molecular and cellular basis of host defense against both attenuated and parental pathogens.

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

“…We report a child with a distinctive form of AR complete IFNAR1 deficiency, with cell surface expression of a non-functional IFNAR1. AR complete IFNAR1 deficiency has been reported as a genetic cause of severe adverse reactions to measles or yellow fever live attenuated vaccines (LAVs) in two unrelated children (42,65). Unlike the IFNAR1 mutations reported in those patients, which led to a loss of cell-surface IFNAR1 expression, the large homozygous deletion in the IFNAR1 gene found in the patients studied here led to the expression of a Cterminally truncated IFNAR1 protein that was nevertheless expressed at the cell membrane.…”

Human genetics of life-threatening influenza pneumonitis

“…It remains a mystery why the disruption of a broad range of IFNs, with different affinities for the receptors and different tissue distributions, results in isolated LAV infection. Immunization with LAVs in early childhood has only been widely practiced for the last 50 years (Poyhonen et al 2019), which is not long enough for selection pressure to have been exerted on the general population. The rarity of IFNAR1 and IFNAR2 deficiencies suggests that type I IFNs are evolutionarily important, but for reasons not entirely understood as yet.…”

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

“…Live (oral) poliovirus vaccine can cause vaccine-associated paralytic poliomyelitis in patients with agammaglobulinemia due to a variety of inborn errors of T or B cells ( Shaghaghi et al, 2014 ). Oral rotavirus vaccine can cause life-threatening dehydration in patients with severe combined immunodeficiencies ( Pöyhönen et al, 2019 ). The measles vaccine strain in the measles, mumps, and rubella (MMR) vaccine can cause disseminated infections in patients with inborn errors of IFNAR2 ( Duncan et al, 2015 ), STAT1 ( Burns et al, 2016 ), or STAT2 ( Hambleton et al, 2013 ; Moens et al, 2017 ), which control cellular responses to various IFNs (type I only in the case of IFNAR2, type I and type III IFNs for STAT2, and all three types for STAT1).…”