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Case for Gonococcal Prevention
Cal MacLennan
Gonococcal Vaccine Project, Jenner Institute, University of Oxford
Meningitis Research Foundation Conference
2 November 2021
1
2 November 2021
Pelvic inflammatory disease : cervicitis,
salpingitis , endometritis.
Accessory gland infection
Peri-hepatitis
Pregnancy morbidity
Disseminated Gonococcal Infection (DGI):
arthritis-dermatitis syndrome
endocarditis, meningitis
Urethritis
Proctitis
Pharyngeal infections
Conjunctivitis
Epididymitis (male infertility)
Abscess of Cowper’s/Tyson’s glands
Seminal vesiculitis
Prostatitis
Many infections asymptomatic:
Complications
of Genital
Infection
Infertility
Ectopic Pregnancy
Spontaneous abortion
Congenital Infection:
- Ophthalmia neonatorum : destructive corneal scarring and blindness
- Skin infections
Common coinfections with other sexually transmitted pathogens
Increase risk to contract and transmit HIV
Gonorrhoea
50-80 % Female
~40 % male
- Sexual transmitted infection
- Caused by: Neisseria gonorrhoeae, gonococcus, GC:
Gram Negative diplococci
Obligate human pathogen
- Second most common bacterial STI
- Global incidence of over 78 million cases
per year 21 % increase incidence between
2005 and 2012 (WHO).
- Rates vary: incidence is 12.5
cases/100,000 population in Europe and
≈6,000 cases/100,000 population in parts of
sub-Saharan Africa
Gonorrhoea
Public Health England. Health Protection Report. June 2018.
- In the UK, there has been a year-on-year increase in cases between 2008 and 2015
Data are estimated numbers of incident cases in millions for chlamydia,
gonorrhoea, syphilis, and trichomoniasis in 2012. Unemo M. The Lancet. 2017
Urgent need for a vaccine
- Resistance to all types of antibiotics used to treat it over the
past decades
- Emergence of multi-drug-resistant strains exhibit high-level
resistance to the expanded-spectrum cephalosporins
(ceftriaxone and cefixime); which are the last remaining options
for empirical first-line monotherapy
- No new single antibiotic options presently availableFirst-line
treatment: ceftriaxone + azithromycin
Gonorrhoea has the potential to become
untreatable (WHO)
Emergence of azithromycin and/or ceftriaxone resistance
Control of N. gonorrhoeae
• Antimicrobial resistance is a major problem:
Quillin SJ, Seifert. Nat Rev Microbiol. 2018
(published 5 October 2018)
Difficulties in vaccine development
- Lack of knowledge of what immune respond might confer protection:
- Variability of gonococcal antigens: phase and antigenic variation difficulty finding targets common to all strains.
- Lack of knowledge on genital tract immunology
- Lack of in vitro correlate of protection : induction of mucosal IgG and IgA antibodies, and a bactericidal serum
response, did not predict protection (Zhu W. Front Microbiol. 2011;2:124).
- Lack of a robust animal model:
17β-estradiol and antibiotics treated BALB/C (or C57/BL6) mice
Host restrictions severely limit the capacity of this model
• Natural infection does not induce protection generation of a non-native immune response
- Antibody production is low and not necessarily protective
- Able to avoid and actively suppress innate and adaptive immune response:
• Elicit a Th17 drive innate inflammatory responses and suppress Th1/Th2-mediated
specific immune responses
• Production of blocking antibodies against conserve antigens: Rmp
• Actively expelling hydrophobic antimicrobial substances: by active efflux pump system
• Resistance to the bactericidal activity of human serum: LOS sialylation and phase
variation, PorB
- Lack of knowledge of the immune response against GC
Vaccines against N. gonorrhoeae
• Vaccines against gonorrhoea
1) Whole cell vaccine sterilized with thimerosal : No efficacy
Sex workers in Nairobi (1973)
2) Pilus vaccine : No efficacy
US Army trial in Korea (1983)
3) Protein I-based vaccine (PorB) vaccine: No efficacy
Medical student volunteers (1986)
Greenberg et al, Canad. J. Publ. Health, 1974
Boslego et al, Vaccine, 1991
Rice et al, In Neisseria 1994
MeNZB: N. meningitidis OMVs vaccine used for meningitis outbreak - 15-30 year olds
31% (95%CI 21-39) estimate effectiveness against gonorrhoea
Replicated in the mouse model with Bexsero (parenteral administration) (IPNC 2018)
•Vaccines against meningococcus
(Lancet, 2017)

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Professor Cal MacLennan

  • 1. Case for Gonococcal Prevention Cal MacLennan Gonococcal Vaccine Project, Jenner Institute, University of Oxford Meningitis Research Foundation Conference 2 November 2021 1 2 November 2021
  • 2. Pelvic inflammatory disease : cervicitis, salpingitis , endometritis. Accessory gland infection Peri-hepatitis Pregnancy morbidity Disseminated Gonococcal Infection (DGI): arthritis-dermatitis syndrome endocarditis, meningitis Urethritis Proctitis Pharyngeal infections Conjunctivitis Epididymitis (male infertility) Abscess of Cowper’s/Tyson’s glands Seminal vesiculitis Prostatitis Many infections asymptomatic: Complications of Genital Infection Infertility Ectopic Pregnancy Spontaneous abortion Congenital Infection: - Ophthalmia neonatorum : destructive corneal scarring and blindness - Skin infections Common coinfections with other sexually transmitted pathogens Increase risk to contract and transmit HIV Gonorrhoea 50-80 % Female ~40 % male - Sexual transmitted infection - Caused by: Neisseria gonorrhoeae, gonococcus, GC: Gram Negative diplococci Obligate human pathogen
  • 3. - Second most common bacterial STI - Global incidence of over 78 million cases per year 21 % increase incidence between 2005 and 2012 (WHO). - Rates vary: incidence is 12.5 cases/100,000 population in Europe and ≈6,000 cases/100,000 population in parts of sub-Saharan Africa Gonorrhoea Public Health England. Health Protection Report. June 2018. - In the UK, there has been a year-on-year increase in cases between 2008 and 2015 Data are estimated numbers of incident cases in millions for chlamydia, gonorrhoea, syphilis, and trichomoniasis in 2012. Unemo M. The Lancet. 2017
  • 4. Urgent need for a vaccine - Resistance to all types of antibiotics used to treat it over the past decades - Emergence of multi-drug-resistant strains exhibit high-level resistance to the expanded-spectrum cephalosporins (ceftriaxone and cefixime); which are the last remaining options for empirical first-line monotherapy - No new single antibiotic options presently availableFirst-line treatment: ceftriaxone + azithromycin Gonorrhoea has the potential to become untreatable (WHO) Emergence of azithromycin and/or ceftriaxone resistance Control of N. gonorrhoeae • Antimicrobial resistance is a major problem: Quillin SJ, Seifert. Nat Rev Microbiol. 2018
  • 6. Difficulties in vaccine development - Lack of knowledge of what immune respond might confer protection: - Variability of gonococcal antigens: phase and antigenic variation difficulty finding targets common to all strains. - Lack of knowledge on genital tract immunology - Lack of in vitro correlate of protection : induction of mucosal IgG and IgA antibodies, and a bactericidal serum response, did not predict protection (Zhu W. Front Microbiol. 2011;2:124). - Lack of a robust animal model: 17β-estradiol and antibiotics treated BALB/C (or C57/BL6) mice Host restrictions severely limit the capacity of this model • Natural infection does not induce protection generation of a non-native immune response - Antibody production is low and not necessarily protective - Able to avoid and actively suppress innate and adaptive immune response: • Elicit a Th17 drive innate inflammatory responses and suppress Th1/Th2-mediated specific immune responses • Production of blocking antibodies against conserve antigens: Rmp • Actively expelling hydrophobic antimicrobial substances: by active efflux pump system • Resistance to the bactericidal activity of human serum: LOS sialylation and phase variation, PorB - Lack of knowledge of the immune response against GC
  • 7. Vaccines against N. gonorrhoeae • Vaccines against gonorrhoea 1) Whole cell vaccine sterilized with thimerosal : No efficacy Sex workers in Nairobi (1973) 2) Pilus vaccine : No efficacy US Army trial in Korea (1983) 3) Protein I-based vaccine (PorB) vaccine: No efficacy Medical student volunteers (1986) Greenberg et al, Canad. J. Publ. Health, 1974 Boslego et al, Vaccine, 1991 Rice et al, In Neisseria 1994 MeNZB: N. meningitidis OMVs vaccine used for meningitis outbreak - 15-30 year olds 31% (95%CI 21-39) estimate effectiveness against gonorrhoea Replicated in the mouse model with Bexsero (parenteral administration) (IPNC 2018) •Vaccines against meningococcus (Lancet, 2017)