WHO calls for vaccine development to tackle ‘silent pandemic’ of AMR
Of the top six bacterial pathogens responsible for AMR deaths, only one, Pnuemoccocal disease (Streptococcus pneumoniae), has a vaccine. The report identifies 61 vaccine candidates in clinical development, including several in late stages, and 94 in active pre-clinical development. But while the report says late-stage vaccine candidates have a high development feasibility, it cautions that most will not be available anytime soon.
“Vaccines are powerful tools to prevent infections in the first place, and therefore have the potential to curb the spread of AMR infections," says the organization. "The AMR vaccine pipeline report aims to guide investments and research into feasible vaccines to mitigate AMR.”
The use of vaccines against AMR
The silent pandemic of antimicrobial resistance is of major growing public health concern, notes the WHO.
Resistant bacterial infections alone are associated with nearly 4.95 million deaths per year, with 1.27 million deaths directly attributed to AMR.
However, AMR covers not only bacterial infections but also viruses, fungi and parasites which change over time and no longer respond to medicines, making infections difficult to treat.
There are 16 vaccine candidates in clinical development against S. pneumoniae and 13 against M. tuberculosis.
Klebsiella pneumoniae has 1 vaccine candidate that recently entered the clinical pipeline, and Escherichia coli, which includes ETEC and ExPEC, has 6 and 4 vaccine candidates respectively.
There are 2 vaccine candidates in the pipeline against Staphylococcus aureus, 6 against Helicobacter pylori, 4 against C. jejuni, 9 against all serovars of Salmonella, and 1 against Neisseria gonorrhoeae.
There are no candidates in clinical development against A. baumannii, Enterobacter spp., Enterococcus faecium, H. pylori or P. aeruginosa.
The six leading pathogens for deaths associated with resistance are Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
A vaccine exists for Streptococcus pneumoniae, while Escherichia coli has a feasible vaccine in development.
Conversely, however, there are no vaccines in development for Acinetobacter baumannii and Pseudomonas aeruginosa.
While it is important to invest in developing new antibacterial treatments, vaccines can also be an important additional tool in addressing AMR thanks to multiple mechanisms, says the WHO.
“First, vaccination against a bacterial infection can reduce transmission of drug-resistant and susceptible strains directly in vaccinated populations and indirectly, in unvaccinated populations, through herd immunity," notes the WHO.
"For example, the introduction of pneumococcal conjugate vaccine (PCV-7) in children in the USA resulted in an 84% reduction in invasive disease caused by the forms of drug-resistant Streptococcus pneumoniae specifically targeted by the vaccine, in children under 2 years of age.
"The same vaccination campaign also reduced invasive pneumococcal disease (IPD) in over-65-year-olds by 49%, despite vaccines not being given to this group.
“Second, by reducing the overall burden of infectious diseases, bacterial and viral vaccines reduce antibiotic use, a key driver of resistance.
"Vaccination against viruses reduces the number of people who are susceptible to secondary bacterial infections and require antibiotic treatment, as well as the number of antibiotics inappropriately prescribed to treat viral infections. Rotavirus vaccination is estimated to prevent 13.6 million antibiotic prescriptions every year for children under the age of 5 in LMICs [low and middle income countries].
While resistance has emerged to every antibiotic that has been introduced, resistance to bacterial vaccines is less of a concern.
"Consequently, they are highly attractive as tools for combatting AMR. Vaccines form part of a sustainable response to AMR, as they prevent infections without selecting for antibiotic resistance.
"Although vaccine-evading strains can evolve in rare cases (e.g. PCVs) and there are concerns regarding novel variants and COVID-19 vaccines, the processes involved tend to be comparatively slow and often do not obliterate the vaccine’s efficacy entirely. Therefore, an effective vaccine can continue to be viable for a long time.”
In 2017, the WHO published its first ever list of antibiotic-resistant ‘priority pathogens’: bacteria that pose the greatest threat to human health.
The most critical group of priority pathogens includes multidrug resistant bacteria that pose a particular threat in hospitals and nursing homes. They include Acinetobacter, Pseudomonas and various Enterobacteriaceae (including Klebsiella, E. coli, Serratia, and Proteus). They can cause severe and often deadly infections such as bloodstream infections and pneumonia.
These bacteria have become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins.
The second and third tiers in the list contain other increasingly drug-resistant bacteria that cause more common diseases such as gonorrhoea and food poisoning caused by salmonella.
There are already vaccines available against four priority bacterial pathogens: pneumococcal disease (Streptococcus pneumoniae), Hib (Haemophilus influenzae type b) Tuberculosis (mycobacterium tuberculosis) and Typhoid fever (Salmonella Typhi).
"Current Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis (TB) do not adequately protect against TB and the development of more effective vaccines against TB should be accelerated," says the WHO report.
"The remaining three vaccines are effective, and we need to increase the number of people receiving them to contribute to a reduction in the use of antibiotics and prevent further deaths.
"The bacteria noted in the priority pathogens list pose a significant threat to public health precisely because of their resistance to antibiotics – but they currently have a very weak vaccine pipeline in terms of the number of candidates and feasibility.
"Vaccines against these pathogens are unlikely to be available in the short term, and alternative interventions should be pursued urgently to prevent resistant infections due to priority bacterial pathogens."
The WHO calls for equitable and global access to the vaccines that already exist, especially among populations that need them most in limited-resource settings.
The report can be read in full here.
The report identified four groups of pathogens with vaccine candidates in various stages of clinical development, and with varying degrees of feasibility for vaccine development.
Group A contains pathogens with vaccines already licensed. These exist against four priority pathogens for AMR: Salmonella enterica ser. Typhi, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Mycobacterium tuberculosis.
"The effectiveness of the vaccine against S. pneumoniae dramatically reduced mortality in the US and Europe in comparison to other regions where the vaccine is not widely available and used. The coverage of authorized vaccines should be increased to maximise their impact on AMR. Current Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis (TB) do not adequately protect against TB and the development of more effective vaccines against TB should be accelerated."
Group B includes pathogens with vaccines that are in late-stage clinical trials with high development feasibility: extraintestinal pathogenic Escherichia coli (ExPEC), Salmonella enterica ser. Paratyphi A, Neisseria gonorrhoeae, and Clostridioides difficile.
"Hence, for two out of the six leading pathogens for deaths associated with AMR, a vaccine either already exists, as for S. pneumoniae, or maybe feasible, as for E. coli. R&D efforts and development of vaccines in late-stage clinical trials should be continued and where possible accelerated."
Group C contains pathogens with vaccine candidates either in early clinical trials or with moderate to high feasibility of vaccine development: enterotoxigenic E. coli (ETEC), Klebsiella pneumoniae, non-typhoidal Salmonella (NTS), Campylobacter spp., and Shigella spp.
"Vaccines against these pathogens might be available in the long term, however, short term solutions to prevent resistance should focus on other interventions to reduce AMR."
Group D contains pathogens with a small number or no vaccine candidates in the pipeline and low vaccine development feasibility: Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., Enterococcus faecium, Staphylococcus aureus, and Helicobacter pylori.
"Vaccines against these pathogens are unlikely to be available in the short term, and alternative interventions to prevent AMR caused by these pathogens should be considered. It is even more worrying that the drug development pipeline for A. baumannii and P. aeruginosa also is insufficient to counter this threat."