Freeing vaccine adjuvants from dangerous immunological dogma

Petrovsky, Nikolai

doi:10.1586/14760584.7.1.7

Cited by 59 publications

(41 citation statements)

References 31 publications

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“…Recent studies have linked the necrotic release of intracellular components to stimulation of the adaptive immune response and adjuvant activities (13)(14)(15). Accordingly, nearly all adjuvants, including alum, trigger cytotoxic effects (19). Based on these findings, we hypothesized that adjuvant-mediated cell death could drive the adaptive immune response.…”

Section: Lysosome-disrupting Agents Trigger a Novel Form Of Pro-mentioning

confidence: 96%

“…Necrotic cell death has been implicated in immune responses against multiple microbial pathogens and in tumor immunity (16 -18). As nearly all immunologic adjuvants have cytotoxic activities, it is conceivable that cytotoxic adjuvants, such as alum, enhance the adaptive immune response through induction of necrosis (9,19,20). Specifically, alum has been associated with necrosis, myofascitis, and granuloma formation at the site of injection.…”

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confidence: 99%

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Cathepsin-mediated Necrosis Controls the Adaptive Immune Response by Th2 (T helper type 2)-associated Adjuvants

Jacobson

Lima

Goldberg

et al. 2013

Journal of Biological Chemistry

112

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Background: Recent evidence suggests that adjuvant-mediated cell death contributes to adjuvant activities. Results: We found that the prototypical adjuvant, alum, triggers a novel form of cathepsin-mediated necrosis. We found that agents that trigger this cell death pathway trigger, like alum, a Th2-biased immune response. We also found that inhibiting this cell death pathway prevented adjuvant-mediated immunity. Conclusion: Selective induction of necrosis is a powerful inducer of adaptive immunity. Significance: Understanding how adjuvant-mediated necrotic cell death controls immunity should improve the design of more powerful but safe adjuvants.

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Section: Lysosome-disrupting Agents Trigger a Novel Form Of Pro-mentioning

confidence: 96%

mentioning

confidence: 99%

Cathepsin-mediated Necrosis Controls the Adaptive Immune Response by Th2 (T helper type 2)-associated Adjuvants

Jacobson

Lima

Goldberg

et al. 2013

Journal of Biological Chemistry

112

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“…Unlike alum adjuvant, Advax does not require a temporal association with the antigen for its adjuvant effect, having an adjuvant effect even when injected 24 h prior to injection of the antigen (25). While additional aspects of the mechanism of action of this unique polysaccharide adjuvant will be important to decipher, the critical attributes for human vaccine adjuvants are efficacy, safety, and tolerability (71,72). Reassuringly, there was no evidence of any local or systemic toxicity from JE-ADVAX immunization, which supports the safety and tolerability data seen in recent human trials (22).…”

Section: Cd8mentioning

confidence: 99%

An Inactivated Cell Culture Japanese Encephalitis Vaccine (JE-ADVAX) Formulated with Delta Inulin Adjuvant Provides Robust Heterologous Protection against West Nile Encephalitis via Cross-Protective Memory B Cells and Neutralizing Antibody

Petrovsky

Larena

Siddharthan

et al. 2013

J Virol

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e West Nile virus (WNV), currently the cause of a serious U.S. epidemic, is a mosquito-borne flavivirus and member of the Japanese encephalitis (JE) serocomplex. There is currently no approved human WNV vaccine, and treatment options remain limited, resulting in significant mortality and morbidity from human infection. Given the availability of approved human JE vaccines, this study asked whether the JE-ADVAX vaccine, which contains an inactivated cell culture JE virus antigen formulated with Advax delta inulin adjuvant, could provide heterologous protection against WNV infection in wild-type and ␤2-microglobulindeficient (␤2m ؊/؊ ) murine models. Mice immunized twice or even once with JE-ADVAX were protected against lethal WNV challenge even when mice had low or absent serum cross-neutralizing WNV titers prior to challenge. Similarly, ␤2m ؊/؊ mice immunized with JE-ADVAX were protected against lethal WNV challenge in the absence of CD8 ؉ T cells and prechallenge WNV antibody titers. Protection against WNV could be adoptively transferred to naive mice by memory B cells from JE-ADVAX-immunized animals. Hence, in addition to increasing serum cross-neutralizing antibody titers, JE-ADVAX induced a memory Bcell population able to provide heterologous protection against WNV challenge. Heterologous protection was reduced when JE vaccine antigen was administered alone without Advax, confirming the importance of the adjuvant to induction of cross-protective immunity. In the absence of an approved human WNV vaccine, JE-ADVAX could provide an alternative approach for control of a major human WNV epidemic.

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“…However, recent investigations of adjuvants with excellent efficacy and safety records in clinical and nonclinical studies and a better understanding of adjuvant toxicity [2,7,118,119] have demonstrated that adjuvants can be designed in ways that maintain potency while avoiding local and systemic toxicity.…”

Section: Final Considerationsmentioning

confidence: 99%