Vaccines as key players in mitigating AMR (Part-II)
- Latest news on vaccine R&D against key bacterial pathogens
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Vaccines are essential in the fight against antimicrobial resistance. World leaders have called for innovation in vaccine-lead development and manufacturing to deal with the pressing problems. With long timelines, licensing new or repurposed vaccines might however seem to be decades away. We have compiled here vaccines against priority bacterial pathogens that might soon be routine. Their implementation and eventual success might set a template for a paradigm shift from reliance of antibiotics to that of vaccines to tackle common pathogens.
In 2017, the World Health Organization (WHO) arrived at a list of high-priority pathogens based on antibiotic resistance, clinical presentation, duration, and the treatment of diseases they cause (1). In addition to a call on developing novel antimicrobials, vaccine development was emphasized. The emphasis gained much thrust in the wake of antimicrobial resistance.
Consequently, the WHO identified and reclassified the high-priority pathogens by the feasibility of vaccine development against them into three groups (2).
Pipeline Feasibility Group A (very high): Pathogens for which licensed vaccines already exist. The focus is to increase the coverage of authorized vaccines.
Pipeline Feasibility Group B (high): Priority pathogens for which a vaccine candidate is in late-stage development. The focus is to accelerate their development.
Pipeline Feasibility Group C (moderate): Priority pathogens for which a vaccine candidate is in early clinical trials or understood in expert reviews. The focus is to generate knowledge on the potential for vaccine use and its impact.
Figure: Categorization of high-priority pathogens based on vaccine development feasibility. Source: (2)
Here, we discuss the vaccines from Group A and Group B that will soon enter the licensing phase or have just been licensed. India and China are significant contributors to the manufacturing and licensing of these vaccines.
Extraintestinal pathogenic Escherichia coli (ExPEC)
The exposure to and consumption of multidrug-resistant pathogens is a reality we are currently gripping. It hit home when these resistant E. coli were identified in supermarket meat samples (3).
E. coli colonization is a significant threat if it happens outside the intestine (extraintestinal), for example, in the bloodstream or urinary tract. Extraintestinal pathogenic Escherichia coli (ExPEC) is responsible for sepsis, urinary tract infections (UTIs), adult bacteremia, neonatal meningitis, and pneumonia. Clinical and economic burden analyses indicates ExPEC to be a major cause of bloodstream infection across China, Japan, South Korea, Taiwan, and Australia (4).
There is a significant increase in mortality when patients have antimicrobial-resistant E. coli infections (compared to susceptible infections). Of particular public health importance, it was estimated that additional 58–130 patients (per 1000) die due to resistant E. coli infections (5). The horizontal transfer of pathogenic fragments across species complicates the problem (6).
Hope arrives in the form of a vaccine candidate, ExPEC9V. In February 2002, the European Medical Association granted ExPEC9V a waiver enabling a faster marketing authorization plan (7).
ExPEC9V, the Johnson & Johnson vaccine candidate, is a nine-valent O-polysaccharide conjugate vaccine for which a Phase 3 clinical trial (NCT04899336) is also underway. It is a bioconjugate vaccine with polysaccharides and adjuvants liked to the bacterial antigen (8).
Salmonella enterica (non-typhoidal serovars)
Non-typhoidal salmonella invasive disease claimed 77,500 lives globally in 2017, with Southeast Asia suffering one-third with 21,500 deaths (9). The disease poses a significant risk to malnourished infants, elderly people, and individuals with HIV and malaria.
CVD 1000, a vaccine candidate by Bharat Biotech in collaboration with the University of Maryland, is undergoing a Phase 1 clinical trial (NCT03981952). It is a trivalent conjugate vaccine targeting S. enterica ser. Enteritidis, ser. Typhimurium, and ser. Typhi linked to tetanus toxoid.
Salmonella enterica ser. paratyphi
With the success of the typhoid conjugate vaccine (10), it is pertinent to address the burden of paratyphoid fever. The global load of paratyphoid fever A was 3.8 million cases in 2019. In Asian countries, paratyphoid fever A is rising as the major cause of enteric fever.
Recently, certain isolates of S.paratyphi A as well as S. typhi have acquired resistance to fluoroquinolones, earlier considered to be highly efficacious antibiotics. These drug-resistant outbreaks were seen in African and South Asian countries in the past decade (11).
South Asian countries including China and India are currently leading the vaccine-based efforts in this area. Lanzhou Institutes of Biological Products in China is currently conducting Phase 2 trials of the O-specific polysaccharide (O:2) conjugated to the tetanus toxoid (O:2-TT) vaccine. This vaccine is projected to be licensed in-country soon and achieve WHO prequalification.
Bharat Biotech, India in collaboration with the University of Maryland is developing CVD 1902, a live oral vaccine. In 2021, the candidate completed its Phase 1 trial (NCT01129453) with it being well-tolerated in 30 participants and reporting no adverse events.
Neisseria gonorrhea
Eighty-two million new cases of gonorrhea occurred globally in 2020, with the majority in the African and Western Pacific regions (12). Undiagnosed and untreated gonococcal infection may be catastrophic as it manifests in reproductive diseases including infertility and a danger to newborn health and survival.
The WHO targets to reduce new cases to 8.2 million per year in 2030 (13). The most significant deterrent to this plan is the multidrug-resistant strain of Neisseria gonorrhoeae. There is an increased call for better surveillance in LMICs as most data on multidrug-resistant gonorrhea come from high-income economies (14, 15).
A meningococcal B vaccine, 4CMenB (Bexsero®), is under Phase 3 clinical trial to examine the prevention of gonorrheal infection in Australian gay and bisexual men (NCT04415424). This vaccine is highly protective against meningitis and is administered as a part of the United Kingdom’s infant vaccination program.
The cross-protection offered by this vaccine presents its potential in certain simulation studies. The studies predict that catch-up vaccination for 14-year-olds can prevent up to 25% of gonorrheal infections in 10 years in the UK (16).
These efforts are being supplemented by entities like CARB-X. For example, a promising initiative by GVGH, a vaccine against invasive non-typhoidal Salmonella (iNTS-TCV) has received total monetary support to the tune of USD 5.4 million from CARB-X. This vaccine is
based on GMMA technology, which utilizes bacterially secreted membrane-enclosed proteins as antigens. The first-in-human (FIH) study for the iNTS-TCV alone received funding of USD 3.2 million from CARB-X.
A team at the Jenner Institute is also supported by a USD 1.7million funding by CARB-X. This research group is in the early stages of development of a vaccine against gonorrhea, with a lead, dmGC_0817560 NOMV. This vaccine is being developed to cover a wide gamut of gonorrhea strains including antibiotic-resistant ones (17).
Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however, this does not claim to be an exhaustive document on the subject. The mention of entities, networks, consortiums, or partnerships is merely to highlight the stakeholders working in the field and does not reflect attestations, validations or promotion of their work. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.
References:
https://www.who.int/publications/i/item/WHO-EMP-IAU-2017.12
Frost I, Sati H, Garcia-Vello P, et al. The role of bacterial vaccines in the fight against antimicrobial resistance: an analysis of the preclinical and clinical development pipeline. Lancet Microbe. 2023;4(2):e113-e125. doi:10.1016/S2666–5247(22)00303–2
https://www.foodsafetynews.com/2023/04/a-group-of-e-coli-found-in-spanish-meat-samples/.
Ohmagari N, Choi WS, Tang HJ, et al. Targeted literature review of the burden of extraintestinal pathogenic Escherichia Coli among elderly patients in Asia Pacific regions. J Med Econ. 2023;26(1):168–178. doi:10.1080/13696998.2023.2169447
MacKinnon MC, Sargeant JM, Pearl DL, et al. Evaluation of the health and healthcare system burden due to antimicrobial-resistant Escherichia coli infections in humans: a systematic review and meta-analysis. Antimicrob Resist Infect Control. 2020;9(1):200. Published 2020 Dec 10. doi:10.1186/s13756–020–00863-x
https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002996-pip01-21
https://www.jnj.com/innovation/meet-janssen-researcher-working-on-human-e-coli-vaccine
GBD 2017 Non-Typhoidal Salmonella Invasive Disease Collaborators. The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;19(12):1312–1324. doi:10.1016/S1473–3099(19)30418–9
A bright future in typhoid vaccines. The Lancet Editorial. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00520-9/fulltext
Genomic epidemiology and antimicrobial resistance transmission of Salmonella Typhi and Paratyphi A at three urban sites in Africa and Asia. Zoe A. Dyson, Philip M. Ashton, Farhana Khanam, Angeziwa Chunga, Mila Shakya, James Meiring, Susan Tonks, Abhilasha Karkey, Chisomo Msefula, John D. Clemens, Sarah J. Dunstan, Stephen Baker, Gordon Dougan, Virginia E. Pitzer, Buddha Basnyat, Firdausi Qadri, Robert S. Heyderman, Melita A. Gordon, Andrew J. Pollard, Kathryn E.Holt, STRATAA Study GroupmedRxiv 2023.03.11.23286741; doi:https://doi.org/10.1101/2023.03.11.23286741
Multi-drug resistant gonorrhoea. World Health Organisation. https://www.who.int/news-room/fact-sheets/detail/multi-drug-resistant-gonorrhoea
Global health sector strategies 2022–2030. World Health Organisation. https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/strategies/global-health-sector-strategies
https://edition.cnn.com/2023/01/19/health/first-us-multidrug-resistant-gonorrhea/index.html
Sánchez-Busó L, Cole MJ, Spiteri G, et al. Europe-wide expansion and eradication of multidrug-resistant Neisseria gonorrhoeae lineages: a genomic surveillance study. Lancet Microbe. 2022;3(6):e452-e463. doi:10.1016/S2666–5247(22)00044–1
Looker KJ, Booton R, Begum N, et al. The potential public health impact of adolescent 4CMenB vaccination on Neisseria gonorrhoeae infection in England: a modelling study. BMC Public Health. 2023;23(1):1. Published 2023 Jan 10. doi:10.1186/s12889–022–14670-z
