Mortality among recipients of the Merck V710 <i>Staphylococcus aureus</i> vaccine after postoperative <i>S. aureus</i> infections: An analysis of possible contributing host factors

McNeely, Tessie; Shah, Najaf A.; Fridman, Arthur; Joshi, Amita; Hartzel, Jonathan; Keshari, Ravi S.; Lupu, Florea; DiNubile, Mark J.

doi:10.4161/hv.34407

Cited by 77 publications

(68 citation statements)

References 22 publications

(22 reference statements)

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“…However, Merck abruptly stopped the study, citing a high rate of adverse vaccine-related events and multiorgan failure in another study (63). The details of these events have yet to be reported (88); however, in nearly all the subjects receiving V710, but not the placebo group, the prevaccination interleukin-2 (IL-2) and IL-17 levels were low, suggesting that some type of aberrant immune response contributed to an inability to resolve subsequent staphylococcal infections (89). Therefore, an understanding of the molecular properties of the NEAT domain can aid in the development of a safe anthrax vaccine.…”

Section: Discussionmentioning

confidence: 99%

Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease

et al. 2016

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Bacillus anthracis is a sporulating Gram-positive bacterium that is the causative agent of anthrax and a potential weapon of bioterrorism. The U.S.-licensed anthrax vaccine is made from an incompletely characterized culture supernatant of a nonencapsulated, toxigenic strain (anthrax vaccine absorbed [AVA]) whose primary protective component is thought to be protective antigen (PA). AVA is effective in protecting animals and elicits toxin-neutralizing antibodies in humans, but enthusiasm is dampened by its undefined composition, multishot regimen, recommended boosters, and potential for adverse reactions. Improving next-generation anthrax vaccines is important to safeguard citizens and the military. Here, we report that vaccination with recombinant forms of a conserved domain (near-iron transporter [NEAT]), common in Gram-positive pathogens, elicits protection in a murine model of B. anthracis infection. Protection was observed with both Freund's and alum adjuvants, given subcutaneously and intramuscularly, respectively, with a mixed composite of NEATs. Protection correlated with an antibody response against the NEAT domains and a decrease in the numbers of bacteria in major organs. Anti-NEAT antibodies promote opsonophagocytosis of bacilli by alveolar macrophages. To guide the development of inactive and safe NEAT antigens, we also report the crystal structure of one of the NEAT domains (Hal) and identify critical residues mediating its heme-binding and acquisition activity. These results indicate that we should consider NEAT proteins in the development of an improved antianthrax vaccine.

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Section: Discussionmentioning

confidence: 99%

Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease

et al. 2016

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“…However, a phase IIB/III clinical trial with the IsdB vaccine (Merck V710) in cardiothoracic surgery patients was stopped prematurely when, despite induction of IsdB antibodies, excessive deaths were noted in the vaccine group among subjects who developed post-operative S. aureus infections (Fowler et al 2013). Subsequent serum cytokine analysis showed that low IL-2 and IL-17 levels post-vaccination correlated with mortality in subjects who later developed S. aureus infections, consistent with a potential T cell-based mechanism although immune analysis after infection to further characterize the associated immune response has not been reported (McNeely et al 2014). …”

Section: Role Of B Cells and Antibodiesmentioning

confidence: 99%

Adaptive Immunity Against Staphylococcus aureus

Karaüzüm

Datta

2016

Current Topics in Microbiology and Immunology

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A complex interplay between host and bacterial factors allows Staphylococcus aureus to occupy its niche as a human commensal and a major human pathogen. The role of neutrophils as a critical component of the innate immune response against S. aureus, particularly for control of systemic infection, has been established in both animal models and in humans with acquired and congenital neutrophil dysfunction. The role of the adaptive immune system is less clear. Although deficiencies in adaptive immunity do not result in the marked susceptibility to S. aureus infection that neutrophil dysfunction imparts, emerging evidence suggests both T cell- and B cell-mediated adaptive immunity can influence host susceptibility and control of S. aureus. The contribution of adaptive immunity depends on the context and site of infection, and can be either beneficial or detrimental to the host. Furthermore, S. aureus has evolved mechanisms to manipulate adaptive immune responses to its advantage. In this chapter, we will review the evidence for the role of adaptive immunity during S. aureus infections. Further elucidation of this role will be important to understand how it influences susceptibility to infection and to appropriately design vaccines that elicit adaptive immune responses to protect against subsequent infections.

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“…A recent analysis of the data from V710 subjects showed that low prevaccination interleukin 2 levels or undetectable preoperative interleukin 17a levels in subjects who acquired postoperative S. aureus infections appeared to be associated with increased mortality. Investigation into data from this trial is continuing, and additional insights into optimal vaccine design will hopefully be gained [42].…”

Section: Staphylococcus Aureusmentioning

confidence: 99%

Vaccines for Healthcare-associated Infections: Promise and Challenge

et al. 2016

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As antibiotic resistance increases and the rate of antibiotic development slows, it is becoming more urgent to develop novel approaches to prevent and mitigate serious bacterial and fungal infections. Healthcare-associated infections (HAIs), including those caused by Clostridium difficile, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenem-resistant Enterobacteriaceae, and Candida species, are a major cause of morbidity, mortality, and healthcare costs. HAIs are also a key driver of antibiotic use. Vaccines directed toward these pathogens could help prevent a large number of HAIs and associated antibiotic use if administered to targeted populations. Despite numerous scientific and operational challenges, there are vaccine candidates in late-stage clinical development for C. difficile, S. aureus, and P. aeruginosa. Basic, preclinical, and early clinical research to develop vaccines for other types of HAIs is also under way. In addition, other prophylactic immune interventions, such as monoclonal antibodies, for several of these pathogens are in advanced development. Here we describe the promise, challenges, and current pipeline of vaccines to prevent HAIs.

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Mortality among recipients of the Merck V710 Staphylococcus aureus vaccine after postoperative S. aureus infections: An analysis of possible contributing host factors

Cited by 77 publications

References 22 publications

Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease

Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease

Adaptive Immunity Against Staphylococcus aureus

Vaccines for Healthcare-associated Infections: Promise and Challenge

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