At Issue

Six reasons we lack an S. aureus vaccine

Infectious Diseases in Children asked Christopher J. Harrison, MD, FPIDS, a physician in the division of infectious diseases at Children’s Mercy Kansas City, to discuss the feasibility of a Staphylococcus aureus vaccine.

All humans acquire S. aureus (SA), up to 60% as commensal bacteria. SA also causes disease, ranging from uncomplicated skin/soft tissue infections (SSTIs) to serious and potentially lethal bone, joint, lung, or bloodstream infections. SA is economically important, costing nearly $5 billion annually just for complicated SSTIs, according to a 2014 study by Suaya and colleagues in BMC Infectious Diseases.

SA infections occur at all ages, but the very young and elderly are at increased risk. Similarly, although healthy individuals are at risk, comorbidities, such as chronic skin problems, being immunocompromised (antibody, neutrophil and/or T-cell deficiencies), indwelling foreign material, and postoperative status, increase risk. Treatment difficulties due to MRSA highlight the need for preventive strategies.

Christopher J. Harrison

Thus, SA is a perfect target for a preventive vaccine. At present, none is available, but not for lack of effort. It is currently unclear which responses are critical for protection against the differing SA strains.

Therefore, vaccine developers initially built on successful vaccine strategies for another gram-positive pathogen (pneumococcus) and tested the candidate vaccines in high-risk populations (eg, patients undergoing dialysis or orthopedic patients with inserted hardware). These initially promising vaccines became very expensive failures. What factors make finding a vaccine so difficult?

  • 1. Targets vary and change. Pathogenic strains contain a variety of temporally and geographically different virulence factors. Further, any single strain may change a virulence factor because of interstrain exchange of the genetic material coding for the many versions of a virulence factor.
  • 2. Anticapsular antibody alone is not enough. A conjugate capsular antigen candidate vaccine similar to pneumococcal conjugate vaccine succeeded in mice, but this conjugated-CP5 and CP8 vaccine failed in human dialysis patients (a high-risk group), according to a 2016 by Giersing and colleagues in Vaccine. This means a successful vaccine will likely need to target multiple facets of SA virulence and immune evasion, for example, some critical noncapsular antigens.
  • 3. Immunopathological responses may occur. Vaccine-induced response to noncapsular antigen vaccine, for example, iron-regulated surface determinant B (IsdB), inadvertently enhanced susceptibility to organ damage during infection. This was likely involved in increased deaths during SA infection among V710 vaccine recipients.
  • 4. A successful vaccine against bacteremia may require different antigens than one preventing SSTI. We learned with pertussis that preventing infection at or near the body surface is very difficult, requiring robust plus durable antibody plus cell-mediated responses. And frequent booster may be needed, as well as adjuvants.
  • 5. No protective threshold is known. Another barrier to a successful vaccine is that even if we choose the correct antigens, no quantitative threshold of response (eg, antibody level or quantitative Th17 response) is a known surrogate of protection. Without an immune surrogate for protection, FDA approval would currently require very large expensive proof-of-efficacy trials.
  • 6. Host genetics may be critical. A vaccine that works for some populations may not work for others. For example, invasive SA disease is higher among blacks than among whites, according to a 2010 study by Kallen and colleagues in JAMA. Linked to this finding seems to be a region on chromosome 6 in the HLA class II region that is statistically decreased in blacks, according to a 2017 study by Cyr and colleagues, published in Genes & Immunity. Therefore, blacks may need a different vaccine than other populations.

So, SA vaccine development is complicated and depends now on developing an understanding of the fundamental interaction of varying hosts and various SA strains. A successful vaccine must overcome SA’s multiple immune evasion mechanisms that can circumvent or subvert vaccine-induced immunity. It is hoped that one candidate in the pipeline will succeed. However, even if the vaccine is placed on a fast track, FDA approval seems at least 5 years away.

Disclosure: Harrison reports being a principle or sub-investigator for studies for which Children’s Mercy Kansas City receives funding from Pfizer, Merck, GSK and Allergan. He also reports receiving travel funding from Pfizer in support of a scientific presentation.

Infectious Diseases in Children asked Christopher J. Harrison, MD, FPIDS, a physician in the division of infectious diseases at Children’s Mercy Kansas City, to discuss the feasibility of a Staphylococcus aureus vaccine.

All humans acquire S. aureus (SA), up to 60% as commensal bacteria. SA also causes disease, ranging from uncomplicated skin/soft tissue infections (SSTIs) to serious and potentially lethal bone, joint, lung, or bloodstream infections. SA is economically important, costing nearly $5 billion annually just for complicated SSTIs, according to a 2014 study by Suaya and colleagues in BMC Infectious Diseases.

SA infections occur at all ages, but the very young and elderly are at increased risk. Similarly, although healthy individuals are at risk, comorbidities, such as chronic skin problems, being immunocompromised (antibody, neutrophil and/or T-cell deficiencies), indwelling foreign material, and postoperative status, increase risk. Treatment difficulties due to MRSA highlight the need for preventive strategies.

Christopher J. Harrison

Thus, SA is a perfect target for a preventive vaccine. At present, none is available, but not for lack of effort. It is currently unclear which responses are critical for protection against the differing SA strains.

Therefore, vaccine developers initially built on successful vaccine strategies for another gram-positive pathogen (pneumococcus) and tested the candidate vaccines in high-risk populations (eg, patients undergoing dialysis or orthopedic patients with inserted hardware). These initially promising vaccines became very expensive failures. What factors make finding a vaccine so difficult?

  • 1. Targets vary and change. Pathogenic strains contain a variety of temporally and geographically different virulence factors. Further, any single strain may change a virulence factor because of interstrain exchange of the genetic material coding for the many versions of a virulence factor.
  • 2. Anticapsular antibody alone is not enough. A conjugate capsular antigen candidate vaccine similar to pneumococcal conjugate vaccine succeeded in mice, but this conjugated-CP5 and CP8 vaccine failed in human dialysis patients (a high-risk group), according to a 2016 by Giersing and colleagues in Vaccine. This means a successful vaccine will likely need to target multiple facets of SA virulence and immune evasion, for example, some critical noncapsular antigens.
  • 3. Immunopathological responses may occur. Vaccine-induced response to noncapsular antigen vaccine, for example, iron-regulated surface determinant B (IsdB), inadvertently enhanced susceptibility to organ damage during infection. This was likely involved in increased deaths during SA infection among V710 vaccine recipients.
  • 4. A successful vaccine against bacteremia may require different antigens than one preventing SSTI. We learned with pertussis that preventing infection at or near the body surface is very difficult, requiring robust plus durable antibody plus cell-mediated responses. And frequent booster may be needed, as well as adjuvants.
  • 5. No protective threshold is known. Another barrier to a successful vaccine is that even if we choose the correct antigens, no quantitative threshold of response (eg, antibody level or quantitative Th17 response) is a known surrogate of protection. Without an immune surrogate for protection, FDA approval would currently require very large expensive proof-of-efficacy trials.
  • 6. Host genetics may be critical. A vaccine that works for some populations may not work for others. For example, invasive SA disease is higher among blacks than among whites, according to a 2010 study by Kallen and colleagues in JAMA. Linked to this finding seems to be a region on chromosome 6 in the HLA class II region that is statistically decreased in blacks, according to a 2017 study by Cyr and colleagues, published in Genes & Immunity. Therefore, blacks may need a different vaccine than other populations.

So, SA vaccine development is complicated and depends now on developing an understanding of the fundamental interaction of varying hosts and various SA strains. A successful vaccine must overcome SA’s multiple immune evasion mechanisms that can circumvent or subvert vaccine-induced immunity. It is hoped that one candidate in the pipeline will succeed. However, even if the vaccine is placed on a fast track, FDA approval seems at least 5 years away.

Disclosure: Harrison reports being a principle or sub-investigator for studies for which Children’s Mercy Kansas City receives funding from Pfizer, Merck, GSK and Allergan. He also reports receiving travel funding from Pfizer in support of a scientific presentation.