Human Ebola virus infection results in substantial immune activation

McElroy, Anita K.; Akondy, Rama; Davis, Carl W.; Ellebedy, Ali H.; Mehta, Aneesh K.; Kraft, Colleen S.; Lyon, G. Marshall; Ribner, Bruce S.; Varkey, Jay B.; Sidney, John; Sette, Alessandro; Campbell, Shelley; Ströher, Ute; Damon, Inger K.; Nichol, Stuart T.; Spiropoulou, Christina F.; Ahmed, Rafi

doi:10.1073/pnas.1502619112

Cited by 271 publications

(360 citation statements)

References 29 publications

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“…For this analysis, we identified PfSPZ-specific T cells by the expression of IFN-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α that was induced by ex vivo stimulation with PfSPZ antigens, and we simultaneously measured the expression of Ki-67 (a marker used to detect recent lymphocyte cell division 25 ; Fig. 5a).…”

Section: Role Of Pfspz Antibodies In Protectionmentioning

confidence: 99%

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Ishizuka¹,

Lyke²,

DeZure³

et al. 2016

Nat Med

318

371

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In 2015 there were an estimated 214 million clinical cases and 438,000 deaths due to malaria 1 , primarily caused by Pf in children in sub-Saharan Africa. A highly effective vaccine is urgently needed to prevent malaria in individuals and to facilitate elimination of malaria from defined geographic areas. To achieve these goals, we established an interim target of >85% sterile protection against Pf infection for >6 months 2 .There is currently no malaria subunit vaccine that approaches this level of protection. The most extensively studied candidate malaria vaccine, RTS,S (a subunit vaccine based on the Pf circumsporozoite protein (PfCSP)), confers sterilizing protection against controlled human malaria infection (CHMI) in about 22% of healthy malarianaive adults 5 months after vaccination 3 . In a phase 3 field study, the efficacy of RTS,S against clinical malaria was 26% and 36% in young infants and children between the ages of 5 and 17 months, respectively, through 38-48 months of follow-up following a fourdose regimen on a 0-, 1-, 2-, and 20-month schedule 4 . Therefore, it is necessary to investigate alternative vaccination strategies that confer long-lived sterilizing protection 5,6 .Sustained sterilizing immunity against the pre-erythrocytic stages of Pf has been observed in humans immunized by wholeparasite approaches using mosquitoes for vaccination 7,8 . In a study An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10 5 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks.To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-g-producing CD8 T cells were present at ~100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

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Section: Role Of Pfspz Antibodies In Protectionmentioning

confidence: 99%

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Ishizuka¹,

Lyke²,

DeZure³

et al. 2016

Nat Med

318

371

View full text Add to dashboard Cite

show abstract

“…Persistent immune activation, rather than direct viral cytopathic effect, has been postulated to lead to some post-EVD sequelae, although the processes are not necessarily mutually exclusive; 26 immune activation might be driven by persistent virus replication or delayed antigen clearance in immune-privileged tissues. In our study, there was no association between the level of viraemia at acute EVD presentation and convalescent arthralgias or auditory symptoms, a finding which suggests a potentially different mechanism of nonocular disease post-EVD.…”

Section: Discussionmentioning

confidence: 99%

Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study

Mattia¹,

Vandy²,

Chang

et al. 2016

The Lancet Infectious Diseases

153

166

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“…Recently, the role of enhanced inflammation in the progression of Ebola virus disease was demonstrated (58). Four Ebola patients who received care at Emory University Hospital presented striking activation of both B and T cells that was manifested by expression of activation phenotypic markers and production of inflammatory cytokines (77). This is a significant observation that is made in humans naturally infected with Ebola virus but not in animals experimentally infected.…”

Section: Repurposing Existing Drugs For Treatment Of Ebola Patientsmentioning

confidence: 99%

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

Haque

Hober

Blondiaux³

2015

Antimicrob Agents Chemother

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c Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre-and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

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Human Ebola virus infection results in substantial immune activation

Cited by 271 publications

References 29 publications

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

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