ROLE OF VACCINES IN PREVENTION AND CONTROL OF RESISTANCE

Prof Victor Lim

Antimicrobial Resistance
Increasing antibiotic resistance globally Antibiotic resistance has adversely affects clinical outcomes increases cost of health care Now acknowledged to be one of the most serious threats to public health Patient safety issue WHO 3rd Global Patient Safety Challenge : Tackling Antimicrobial Resistance

Drivers of Antimicrobial Resistance

Overuse of antibiotics Exerts a selection pressure Favours the proliferation of resistant strains Lack of infection control Allows the spread of resistant strains

The Antibiotic Pipeline is drying up

Infections due to multiply resistant organisms are now frequently encountered The antibiotic pipeline is drying up. One strategy is to use vaccines to prevent infections caused by resistant organisms

Vaccines as a strategy to contain antibiotic resistance

Vaccines Prevent colonisation by organisms Prevent infection by organisms Reduction of colonisation Reduces exposure of the organisms to antibiotics and consequently the development of resistance Prevention of infection Reduces the necessity to treat with antibiotics and thereby reduces antibiotic usage Reduces transmission of organisms in the community

Vaccines as a strategy to contain antibiotic resistance

Public Health Authorities are increasingly acknowledging the role of vaccines in the strategy to contain antibiotic resistance a wide range of measures is needed to ensure that currently available antibiotics remain effective for as long as possible, such as effective vaccines to prevent infections
Council conclusions on innovative incentives for effective antibiotics. Council of the European Union, 2009

Case study : Pneumococcal Vaccine

Immunisation with the 7-valent conjugate pneumoccocal vaccine (PCV7) shown to reduce burden of antibiotic resistance due to strains covered by the vaccine. In US rates of resistant invasive pneumococcal disease decreased after introduction of the vaccination programme in 2000
Kyaw MH et al. N Engl J Med 2006; 354:1455

Case study : Pneumococcal Vaccine

Vaccination reduces the transmission of resistant strains and therefore colonisation among the young children Vaccination associated with reduction in antibiotic use Benefit extends to non-immunised as shown by lower carriage rates of resistant strains among nonimmunised family members
Klugman K. Clin Infect Dis 2004; 39:649

Case study : Pneumococcal Vaccine

Pneumococcal resistance rates declined in the period 20012004 However there was a significant rebound for the period 20042007 Due to the emergence of a resistant clone 19A not covered by PCV7

Dagan R. Clin Microbiol Infect 2009; 15(S3):16

Case study : Pneumococcal Vaccine

In a Dutch study infants who received PCV7 were more likely to acquire nasopharyngeal carriage of serotype 19A compared to those who were unvaccinated

Van Gils EJM et al. JAMA 2010; 304: 1099

Case study : Pneumococcal Vaccine

Capsular switch may be induced by vaccination Emergence of antibiotic resistance in non-PCV7 strains due to antibiotic pressure Recent introduction of a 13-valent pneumococcal conjugate vaccine (PCV13) which includes 19A However this may result in the emergence of nonPCV13 strains Vaccine strategy needs to complemented by good antibiotic stewardship
Nzenze et al. South Afr J Epidemiol Infect 2011;26:253

Influenza vaccine and antibiotic use

Universal influenza immunization in Ontario was associated with reduced influenza-associated antibiotic prescriptions. Rates of influenza-associated antibiotic prescriptions decreased from 17.9 to 6.4 per 1000 people (RR, 0.36; 95% CI, 0.260.49)

Kwong JC et al. Clin Infect Dis 2009; 49:750

 Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumanni Pseudomonas aeruginosa Enterobacter sp
IDSA Report on Development Pipeline CID 2009;48 : 1-12

Staphylococcus aureus
Staphylococcal vaccine An early trial of a conjugated Staphylococcus aureus vaccine (StaphVAX) showed some promise in conferring partial protection to patients on hemodialysis Results from a later, larger Phase III trial were unfortunately not as encouraging. A clinical trial of another staphylococcal vaccine (V710) was abandoned in 2011 after it failed to show any benefit.
Shinefield H et al.. New Engl J Med 2002; 346:491-6.

Pseudomonas aeruginosa
Pseudomonas aeruginosa is a major cause of HAI Pan resistant strains are not infrequently encountered Potential targets for a vaccine Flagella Pili Outer membrane proteins Lipopolysaccharides Exotoxin A Proteases
Sharma A et al. Human Vaccin 2011; 7:999

Pseudomonas aeruginosa
Numerous attempts to develop a vaccine against Pseudomonas aeruginosa. Whole cell vaccines Live attenuated Salmonella expressing Pseudomonas antigens Flagella vaccines Pili vaccines Exotoxin A toxoid Adenovirus based vaccine Although many pre-clinical trials have been conducted, there are very few clinical trials No Pseudomonas aeruginosa vaccine is currently licensed for clinical use
Sharma A et al. Human Vaccin 2011; 7:999

Acinetobacter baumanni
Treatment of Acinetobacter baumannii infections has become a serious clinical challenge due to the emergence of highly resistant strains Efforts have begun in developing a vaccine An inactivated whole cell vaccine has been shown to confer protection in a murine model of disseminated sepsis
McConnell MJ et al. Vaccine 2010; 29:1

An outer membrane complex vaccine protected mice when inoculated with clinical strains of Acinetobacter baumannii
McConnell MJ et al. Infect Immun 2011; 79:518

Various other initiatives including passive immunisation, use of other targets No clinical vaccine trials yet

Klebsiella pneumoniae
K pneumoniae is a common cause of HAI and a major resistance problem ESBL, NDM-1, KPC Attractive as a goal for vaccine development 5 main virulence factors that can serve as targets for the vaccine

Podschun R. Clin Microbiol Rev 1998; 11:589

Klebsiella pneumoniae
Effort have largely concentrated on 2 surface components Lipopolysaccharide Capsular polysaccharide Passive immunisation antibodies to K antigens capsular polysaccharide Antibodies to O antigens (lipopolysaccharide) Active immunisation Whole cell Bacterial lysate Protein based (fimbria, outer membrane proteins) Lipopolysaccharide Conjugate polysaccharide None in any advanced stage of clinical trials
Ahmad TA et al. Vaccine 2012;30:2411

Enterococcus
Vancomycin resistant enterococci (VRE) continues to be a major cause of HAI Incidence of VRE infections increasing in Asia Potential targets for vaccines in Enterococcus Capsular polysaccharide antigens Surface proteins Not much development in enterococcal vaccines

Clostridium difficile
Clostridium difficile infection (CDI) is becoming an important cause of morbidity and mortality in health care facilities Nearly 95% of CDI cases are healthcare associated; majority in nursing homes

Kyne L et al. N Engl J Med. 2000:342;390.

Vaccines to prevent CDI

Gerding DN, Discovery Medicine 2012; 13:75-83,

CDI Vaccines under development

Gerding DN. Available at www.nfid.org/gmnode/2548.aspx. Accessed on 2 Oct 2012

Conclusions
Increasing antibiotic resistance and the lack of new agents in the antibiotic pipeline makes vaccination an attractive strategy to meet this challenge Vaccines can help meet the challenge of antibiotic resistance by Preventing colonisation and infection by resistant bacteria Treating resistant infections as adjuncts to antibiotics Limit the transmission and spread of resistant bacteria Decrease the use of antibiotics Many initiatives in the development of vaccines to prevent infections caused by resistant organisms Still in the early stages of such development Currently still no vaccine licensed for use to prevent resistant HAIs