Immunoprophylactics and Immunotherapeutics: Focus on S. aureus
Abstract & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
The inevitability of progression of bacterial resistance to antibiotics used in the clinic and other settings dictates the need for approaches that go beyond antimicrobial stewardship and the development of new antibiotics. These include the prevention of infection by means such as vaccination and use of passive immunoprophylaxis, as well as the development of immunotherapeutics that are not subject to the mechanisms of resistance that affect small molecule antimicrobials.
Prevention of infection is indisputably the optimal means of dealing with the problem of antimicrobial resistance. Vaccines currently in use have been very effective in the prevention of several bacterial infections, but these have not been aimed at multidrug-resistant pathogens. Potential vaccine target bacterial pathogens exhibiting antibiotic resistance include organisms such as Mycobacterium tuberculosis, Helicobacter pylori, Clostridium difficile, Pseudomonas aeruginosa, and Staphylococcus aureus. I will focus here on the last mentioned.
S. aureus, as a consequence of both its increasing prevalence and worsening antibiotic resistance, is a prime potential vaccine target. Initial experience targeting this organism has, however, been disappointing. For example, despite initial evidence suggesting efficacy in the prevention of bacteremia in chronic hemodialysis patients, a capsular polysaccharide vaccine failed in a subsequent larger Phase III trial. In recognition of the need, however, at least one other vaccine, V710, which targets S. aureus iron surface determinant B (IsdB), is being evaluated in early phase trials in cardiac surgery and orthopedic implant patients. Some of the target populations that could potentially benefit from a vaccine against S. aureus are listed in the Table 1.
One reason for the failure of the capsular vaccine may have been the relatively immunocompromised status of chronic dialysis patients. This and other vaccine may prove to have greater efficacy in individuals without evident immune deficiency. The emergence of community-acquired, methicillin-resistant S. aureus (MRSA) infection as a frequent cause of recurrent infection in previously healthy individuals provides a potential target population likely to have a more robust response to vaccination.
It is also likely, given the complexity of the panoply of means by which S. aureus is able to avoid the innate immune response, that an effective vaccine will have to target multiple virulence factors rather than just one.
The development of this and other bacterial vaccines requires adequate funding of basic and translational work and, in circumstances in which the target population is limited (eg, P. aeruginosa infections), significant incentives to industry. Successful vaccine development will, however, be a critical element of any successful attack on the problem of antibiotic resistance.
A complementary method of prevention of infection with multidrug-resistant pathogens is that of passive immunoprophylaxis in defined populations, particularly those who are unlikely to have an adequate immunological response to vaccination and/or for whom there is inadequate time for a vaccine response prior to a potential danger period. Such individuals may include those undergoing urgently required cardiac or orthopedic surgery, as well as burn patients and other patients already severely immunocompromised or about to become so. Finally, agents developed for passive immunoprophylaxis may also prove to be effective as therapeutic agents. With reference once again to S. aureus, several agents are undergoing current investigation (see Table 2).
In summary, the development of vaccines and immunoprophylactics capable of preventing infection with multidrug resistant pathogens will be a necessary element in the struggle against antibiotic resistance. In addition, immunotherapeutics have the capability to save lives of patients infected with such pathogens.