A scrub typhus vaccine presents a challenging unmet need

Abstract

Scrub typhus caused by the obligately intracellular bacterium, Orientia tsutsugamushi, is a major cause of life-threatening acute undifferentiated febrile illness in eastern Asia and the islands of the Western Pacific and Indian oceans. Since the estimation of an incidence of 1 million cases annually two decades ago, the number of cases has increased substantially in endemic regions, reappeared where the disease was forgotten, and spread northward. Trombiculid mites are both reservoir and vector. Despite 80 years of efforts to develop a vaccine, there is none. Protective immunity is mediated by antibodies and CD8 and CD4 T cells. Previous efforts have failed because of gaps in understanding immunity to O. tsutsugamushi, particularly the requirements for vaccine-induced immunity, lack of knowledge regarding immune memory in scrub typhus, and lack of attention to addressing the issue of cross-protection between strains. There are numerous strains of O. tsutsugamushi, and modestly durable immunity is strain-specific. Antibodies to the strain that caused infection are protective against challenges with the homologous strain but, despite reactivity with other immunodominant antigens, the immune serum does not protect against heterologous strains. Among the antigens detected by western immunoblot in immune sera (22-, 47-, 56-, 58-, and 110 kDa proteins), only the 56 kDa protein stimulates strong protection. This protein contains four hypervariable regions which are likely, on the basis of limited data, to be the targets of neutralizing antibodies. However, a method that definitively detects neutralizing antibody has yet to be developed. Only one study has used genomic data to pursue the discovery of protective antigens. Three conserved autotransporters were identified, and only immunization with ScaA provided protection against the homologous strain, but only 40% of animals were protected against challenge with a heterologous strain. A multiplex vaccine containing conformational antigens of the hypervariable regions of the 56 kDa protein of the strains of the greatest clinical and epidemiological importance, as well as conserved regions of the 56 kDa protein, ScaA, and other protective antigens identified by future genomic and bioinformatics methods should be developed and tested.

Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice

“…Our conclusion of host-dependent susceptibility is consistent with other murine models for comparison between Karp and Gilliam, which overwhelmingly show Karp is more virulent in the animals, regardless of the routes of infection or mouse strain/stock used [ 13 , 26 , 27 , 43 , 47 – 50 ]. For non-human primate models, only a few comparison studies between bacterial strains have been conducted.…”

“…Scrub typhus is a seriously understudied tropical infectious disease, which has recently emerged outside of its traditional geographic areas [ 42 , 43 ]. Understanding cellular immune responses in the major target organs and during acute stages of infection with different Ot strains has been difficult and requires urgent attention.…”

Phylogenetic and immunological investigations of complete TSA56 ORF of Orientia tsutsugamushi present in acute encephalitis syndrome cases from eastern Uttar Pradesh, India

“…The major immunogen of OT that evokes neutralising antibodies in hosts is the 56-kDa type-specific antigen (Jeong et al 2012 ). Further, this protein contains four hypervariable which provide the most important information for genetic differentiation and immunological studies within the Orientia genus (Kelly et al 2009 ; Walker and Mendell 2023 ).…”

Designing Combinatorial Multiepitope Vaccine Candidates against Scrub Typus by a Proteome-wide Immunoinfomatics Approach.

“…Ot infects peripheral dendritic cells in skin, and infection results dermal and epidermal necrosis leading to formation of ulcer, which is the preliminary sign of infection. Subsequently Ot spread through lymphatic system and infect endothelial cells systemically 6 . Typical symptoms like headache, fever, myalgia, generalized lymphadenopathy, transient hearing loss, and rash onset following the systemic infection.…”

“…Typical symptoms like headache, fever, myalgia, generalized lymphadenopathy, transient hearing loss, and rash onset following the systemic infection. If untreated the infection might progress to cause severe ailments including respiratory distress, gastrointestinal haemorrhage, and renal failure 6 . Variation in severity and fatality have been recorded for outbreaks ranging from self-limiting to a more severe condition with a case fatality rate of 6% in absence of chemotherapeutic intervention and 1.5% with treatment.…”