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Vaccine research for gonococcal infections:

where are we?
a

Ann E Jerse, Carolyn D Deal

a

Department of Microbiology
and Immunology, F. Edward
Hebrt School of Medicine,
Uniformed Services University,
Bethesda, Maryland, USA
b
Sexually Transmitted Disease
Branch, National Institute of
Allergy and Infectious Diseases,
National Institutes of Health,
Bethesda, Maryland, USA
Correspondence to
Professor Ann E Jerse,
Department of Microbiology
and Immunology, F. Edward
Hebrt School of Medicine,
Uniformed Services University,
4301 Jones Bridge Rd.
Bethesda, MD 20814-4799,
USA; ann.jerse@usuhs.edu
Received 19 June 2013
Revised 28 August 2013
Accepted 11 September 2013

ABSTRACT
Gonorrhoea continues to seriously impact human society
with an estimated 106 million new infections occurring
annually. The consequence of gonorrhoea on
reproductive and neonatal health is especially concerning
as is its role in the spread of HIV. Current control
measures rely on the identication and treatment of
infected individuals and their sexual contacts. The
success of this strategy, which is already inadequate, is
lessened by poor diagnostic capabilities in many parts of
the world and challenged by the rapid emergence of
antibiotic-resistant strains. The potential of untreatable
gonorrhoea is now real, and a gonorrhoea vaccine
is seriously needed. Historically, gonorrhoea vaccine
research has been hampered by the antigenic variability
of the gonococcal surface, a lack of known protective
mechanisms, and the absence of a small laboratory
animal model for testing candidate vaccines and
manipulating host responses. Here we discuss recent
advances that have rekindled research efforts towards
a gonorrhoea vaccine. Several conserved and
semiconserved vaccine antigens have been identied that
elicit bactericidal antibodies or inhibit target function.
A mouse genital tract infection model is available for
systematic testing of vaccines, and transgenic mice have
been developed to relieve host restrictions. Additionally,
several immunological advances have been made
including the identication of mechanisms by which
Neisseria gonorrhoeae suppresses the adaptive response
and the demonstration that Th1 responses clear
experimental infection in mice and induce a protective
memory response. We also discuss important issues with
respect to product development that must be considered
when entering the vaccine pipeline.

GONORRHOEA: OLD AND NEW CONCERNS, AND

THE SERIOUS NEED FOR A VACCINE Gonorrhoea

To cite: Jerse AE, Deal CD.

Sex Transm Infect 2013;89:
iv63iv68.

is an ancient disease that has seriously impacted

reproductive and neonatal health since at least
Biblical times. In the modern age, gonorrhoea is
accompanied by the additional concerns of
increased spread of HIV and the rapid emergence
and global spread of antibiotic-resistant strains.
Increased resistance to the extended-spectrum
cephalosporins and treatment failures have led to
the recent recommendation of dual therapy as a
rst-line treatment for gonorrhoea. Based on the
evolutionary history of this organism, it is likely
that this strategy will eventually be ineffective. This
alarming situation prompted WHO to issue a
global action report in 2012 that documents the
disease burden of gonorrhoea in the world.
Currently, 106 million cases of gonorrhoea are esti1
mated to occur annually worldwide. The majority
of infections are uncomplicated mucosal infections

Jerse AE, et al. Sex Transm Infect 2013;89:iv63iv68. doi:10.1136/sextrans-2013-051225

of the urogenital tract, pharynx and rectum.

Ascended infections (eg, endometritis, salpingitis,
and epididymitis) are more complicated, and gonococcal pelvic inammatory disease (PID) and the
related complications of infertility, ectopic pregnancy, and chronic pelvic pain constitute the major
morbidity and mortality associated with gonorrhoea. Gonorrhoea during pregnancy increases the
risk of ophthalmia neonatorum in neonates, an
acute conjunctivitis that can lead to blindness.
Pregnant women with gonorrhoea also have
increased risk of premature rupture of membranes
and preterm delivery, which can lead to low birthweight babies and chorioamnionitis complicated by
septic abortion. Disseminated gonococcal infection
(DGI) occurs in up to 0.53% of individuals with
2
mucosal infections.
Clearly, gonorrhoea continues to plague humankind, and new control strategies are seriously
needed. Women and neonates suffer disproportionately from disease, and the incidence of gonorrhoea
is highest in developing countries and in lower
socioeconomic groups within industrialised countries. Current control measures rely on the identication and treatment of infected individuals and
their sexual contacts. Unfortunately, the usefulness
of this approach is threatened by antibiotic resistance and challenged by poor diagnostic capabilities
in parts of the world where syndromic management
is used in the absence of microbiologic culture or
molecular diagnostic techniques.1 To curb the
potential threat of untreatable gonorrhoea, public
health agencies, professional societies and nongovernmental organisations have issued a call for
new antimicrobials against this pathogen. However,
given the complexity of the antimicrobial development process, the time and resources needed to
develop products, and the rapidity by which
Neisseria gonorrhoeae develops resistance to newly
introduced antibiotics, a rational case to pursue
vaccine development can be made to truly have a
long-term impact on public health. Here we discuss
research progress and challenges in this area and
describe some recent sophisticated advances in the
eld of vaccinology that may facilitate the development of gonorrhoea vaccines. We also discuss
important issues inherent to product development
and evaluation.

VACCINE ANTIGENS
Early vaccine studies
Gonorrhoea vaccine research was an active area of
investigation four decades ago. Optimism was high
with the success of capsule-based meningococcal
vaccines and the promising demonstration that
experimental urethral infection in chimpanzees
iv63

Supplement
reduced susceptibility to reinfection. Two unsuccessful eld
trials were conducted during this time. A parenteral heat-killed
whole-cell vaccine was tested in Inuit subjects in Canada, which
yielded no protection. In another trial, parenteral intradermal
delivery of a puried pilin vaccine failed to protect high-risk US
military personnel in Korea, most likely due to pilin antigenic
variation (reviewed in3).
With time, gonorrhoea vaccine research began to wane.
Chimpanzees were no longer available for vaccine studies,
and investigators were frustrated by the antigenic variability
of the gonococal surface and the absence of known correlates of
protec- tion. Additionally, the lack of a small laboratory
animal model made it difcult to test candidate antigens and
study immune responses. Many investigators turned their
attention towards unravelling the genetic basis of antigenic
variation in the gonococ- cus. This era of discovery, which was
impressive in its use of the nascent tools of molecular biology,
resulted in N gonorrhoeae becoming a leading paradigm of a
pathogen that uses phase and antigenic variation of surface
molecules to adapt to its host. The advent of molecular biology
also fuelled molecular pathogenesis research, a consequence of
which is the identication of surface molecules that could be
targeted by a vaccine to block or interfere with infection (table
1). Many of these antigens are stably expressed and
conserved, and for some semiconserved antigens, conserved
functional regions have been identied against which vaccineinduced immune responses might be directed.

Table 1

Current antigens under development

Potential vaccine targets in N gonorrhoeae include surface molecules that mediate adherence to, or uptake by, host cells such as
4
PilC, the type 4 pilus-associated adhesin and PilQ, the secretin
5
through which pili are extruded. Another colonisation factor
that could be targeted is the major gonococcal porin (PorB),
6 7
which is involved in invasion of host cells While there is antigenic heterogeneity among surface-exposed PorB loops between
strains, the identication of conserved domains that confer
PorB-mediated functions could direct the successful development of broadly reactive PorB antigens. Once colonisation is
established, the formation of biolms may stabilise colonisation
and protect against host innate defenses. Several gonococcal
factors are required for efcient biolm formation including
8
nitrite reductase (AniA). AniA is required for anaerobic growth
of N gonorrhoeae in the presence of nitrite and is unusual in its
surface exposure. Ani-A-specic antibodies were detected in
serum from patients with PID or DGI and anaerobic growth is
likely to be important in various body sites inhabited by N
9
gonorrhoeae, particularly the female upper genital tract. In
support of AniA as a vaccine target, Jennings and colleagues
recently reported that antibodies against recombinant AniA
protein lacking the immunodominant glycosylated C-terminus
10
inhibit nitrite reductase activity.
Nutrient acquisition systems have also been identied that
could be developed as nutritional vaccines. The gonococcal

Potential gonorrhoea vaccine antigens

Functional class

Description

Reference number

Colonization
PilC

Pilus-associated adhesin; phase variable expression, variable and conserved regions

PilQ

Outer membrane channel through which pili are extruded; stable expression and antibodies against meningococcal
PilQ are bactericidal

PorB

Major porin, two serogroups (PorB1A and PorB1B), stable expression; involved in gonococcal invasion of cervical cells
through the C3R integrin; PorB1A molecules directly mediate uptake through the SREC-1 receptor

6 7

Opa proteins

Phase variable; 810 antigenically distinct Opa proteins per strain; peptide antigens may be used to avoid
immunosuppressive domains; a cyclic peptide corresponding to the semivariable (SV) loop recognises Opa
proteins with as many as 68 amino acid differences in this loop

OmpA
Surface-exposed, stably expressed, highly conserved. Mediates invasion of cervical and endometrial cells
Nutrient acquisition
TbpA, TbpB

Transferrin receptor; TbpA and TbpB are highly and semiconserved, respectively. Purified TbpA or TbpB induce
bactericidal antibodies in mice that block growth in the presence of Tf as a sole iron source

LbpA, LpbB

Lactoferrin receptor; antibodies against N meningitidis homologues are bactericidal

TdfJ
Iron-induced zinc transporter; antibodies against the meningococcal homologue (ZnuD) are bactericidal
Evasion of innate defenses
MtrE
Surface-exposed channel of the MtrC-MtrD-MtrE and FarA-FarB-MtrE active efflux pumps; stable expression and
highly conserved; antibodies to recombinant MtrE are bactericidal
Lst
2,3 sialyltransferase; catalyses the addition of host-derived sialic acid to the LNT species of LOS; protects
gonococci from complement, non-opsonic uptake by neutrophils and antimicrobial peptides. Antibodies to purified
Lst reduce sialylation
PorB
In serum resistant strains, PorB binds soluble negative regulators of the complement cascade (C4b-binding
protein, factor H) to down-regulate complement activation at the gonococcal surface
Other
2C7 epitope
Bactericidal LOS epitope; phase variable but expressed by >95% of isolates. Antibodies to a 2C7 peptide mimetic
are bactericidal and opsonophagocytic and active and passive protection was demonstrated in mice
AniA
Nitrite reductase; surface-exposed, conserved; induced by low O2 tension and the presence of nitrite. Required for
anaerobic growth and biofilm formation; plays a role in serum resistance. A truncated AniA protein that lacked
the glycosylated C-terminus induced antibodies that inhibited nitrite reductase activity
OpcA
Stably expressed in N gonorrhoeae. OMV from N meningitidis with a phase-locked on opcA gene is a
candidate meningococcal vaccine
NspA
Stably expressed, highly conserved. Meningococcal NspA is protective in mouse model of meningococcal infection
Outer
Can be engineered to stabilise the expression of phase variable or regulated antigens and increase the diversity of
membranes
antigenic variants present. An outer membrane preparation was protective against N gonorrhoeae in a mouse model

26

27

28

13
29 30

(AJ DeRocco and AE Jerse,

unpublished data)
16 17

31

20 32

810

33 34
35
3

Supplement
transferrin (Tf ) receptor (TbpA and TbpB) or lactoferrin (Lf
) receptor are required for experimental urethral infection
11
of male volunteers.
Intranasal immunisation of mice with
TbpA and TbpB proteins fused to cholera toxin subunit B
induces high titre, specic vaginal IgG and IgA antibodies and
bacteri- cidal serum antibodies that inhibit growth of N
gonorrhoeae in media containing Tf as the sole source of iron
12
(reviewed in ). Fifty percent of N gonorrhoeae strains also
express a Lf receptor and the LbpA subunit
of the
meningococcal Lf receptor, which is relatively conserved,
induces bactericidal antibodies. These antibodies have limited
13
cross-reactivity ; however, recent struc- tural models of the
neisserial Lf receptor could facilitate the design of vaccines
14
against conserved functional domains.
Vaccines that cripple the capacity of N gonorrhoeae to evade
host innate defenses also may be effective. N gonorrhoeae expels
hydrophobic antimicrobial substances that bathe mucosal surfaces (eg, fatty acids, long-chain faecal lipids, antimicrobial peptides, progesterone, bile salts) through the MtrC-MtrD-MtrE or
FarA-FarB-MtrE active efux pumps. The MtrC-MtrD-MtrE
system is critical for murine infection and plays a role in
15
antibiotic resistance. MtrE, the outermost component of the
MtrC-MtrD-MtrE and FarA-FarB-MtrE pumps has two
surface-exposed loops that could be targeted in a vaccine.
Immunisation of mice with recombinant MtrE results in surface
binding, bactericidal antibodies that recognise a variety of gonococcal strains (AJ DeRocco and AE Jerse, unpublished observation). Another surface-exposed factor that protects against host
innate defenses is gonococcal -2,3-sialyltransferase (Lst), which
catalyses the addition of host-derived sialic acid to the lactoneotetraose (LNT) species of lipooligosaccharide
(LOS).
Antibodies against puried Lst reduce the level of sialylation,16
and thus, could increase susceptibility to opsonic uptake by neu17
trophils and complement-mediated bacteriolysis. The importance of Lst during infection is supported by the demonstration
that an Lst-decient mutant is attenuated for murine genital
tract infection.18
Other promising vaccine targets include the 2C7 LOS
epitope. Rice and colleagues showed that antibodies against a
2C7-OS peptide mimic are highly bactericidal and promote
opsonophagocytic killing of N gonorrhoeae. Recently, intraperitoneal immunisation of mice with a multiantigenic form of the
2C7-OS peptide mimic was reported to protect mice from subsequent challenge as did passive delivery of 2C7 monoclonal
19 20
antibody.
Another exciting advancement that may guide gonococcal
vaccine research is the development of outer membrane vesicle
(OMV) vaccines against Neisseria meningitidis group B. The
4CMenB vaccine consists of OMV with three added protein
21
antigens identied by reverse vaccinology. None of the three
proteins ( fHBP, NHBA and NadA) in the 4CmenB vaccine
are predicted
to
be
suitable
vaccine
targets
for
22
gonorrhoea.
However, similar non-biased proteomic or genomic screens to
identify effective vaccine antigens could be applied to gonorrhoea vaccine research. Alternatively, gonococcal OMVs could
be prepared from strains that express detoxied LOS, lack
immunosuppressive or blocking antigens, and constitutively
express transcriptionally regulated proteins that are known to be
expressed during infection such as AniA and the Tf and Lf
receptors.

IMMUNISATION AND CHALLENGE MODELS

N gonorrhoeae is highly adapted to its human host, a characteristic that challenges animal modelling of gonorrhoea. Currently,

there are two gonococcal genital tract infection models that can

be used in immunisation and challenge studies. Experimental

urethral infection of male volunteers is a well-characterised
model that is highly relevant to natural infection.11 Modern
technologies can now be applied to the human challenge model,
which has been used for over 60 years, to obtain valuable information on host responses to vaccination or bacterial challenge at
the protein or transcriptional level in urine or genital tract secretions. Limitations to the human model include its feasibility in
most research settings, and the possibility that vaccine studies in
male subjects may not accurately predict vaccine efcacy against
cervical, ascending or disseminated infections.
Experimental infection of female mice can also be used to
assess gonococcal vaccine efcacy.3 Female mice are transiently
susceptible to N gonorrhoeae during the proestrus stage of the
oestrous cycle; treatment with 17-estradiol and antibiotics prolongs colonisation of the lower genital tract for at least
1012 days and ascending infection occurs in 1720% of mice.
BALB/c mice develop an inammatory response to infection
that is characterised by the inux of vaginal neutrophils.
Infection persists during periods of inammation, and similar to
human infection, mice have a poor humoral response to infection, can be reinfected with the same strain, and show no evi18
dence of memory response. Several host restrictions limit the
capacity of experimental murine infection to mimic human neisserial infections. For example, the human carcinoembryonic
antigen-related cell adhesion molecules (CEACAMs) and the
elusive pilus receptor are not expressed in mice. The gonococcus also cannot obtain iron from murine Tf or Lf. Of particular
relevance to vaccine testing are host restrictions in soluble regulators of the complement
cascade ( factor H, C4bbinding protein), the absence of IgA1, the substrate of
gonococcal IgA1 protease, and the opsonophagocytic receptor
for IgA, FcR (CD89). Transgenic mice can relieve some host
restrictions and mouse strains that express human CEACAMs
or Tf have been
18
developed.
Alternatively, puried factors, such as human
fH,
C4BP, or Tf could be administered to mice during the challenge
phase of vaccine experiments to reproduce a more human-like
state. This approach would be particularly useful for vaccines
that are designed to block interactions with soluble
host-restricted factors such as Tf receptor vaccines.

THE IMMUNE RESPONSE TO GONORRHOEA

Induction of vigorous innate, but not adaptive, responses
Symptomatic gonococcal infections are characterised by
purulent exudates that contain neutrophils with intracellular
diplococci. Inapparent infections are common, including most
pharyngeal and rectal infections and 5080% of female genital
tract infections. Proinammatory cytokines and chemokines are
elevated in experi- mentally infected men with urethritis, but
were not detected at levels higher than uninfected controls in
naturally infected women unless coinfected with another sexually
transmitted pathogen. The reason for the high rate of
inapparent infections is not known; body site may play a role,
and in women, hormonal inuences may affect symptomology
(reviewed in3). Recently, Russell and col- leagues demonstrated
that the Th17 pathway was responsible for the inammatory
response induced by N gonorrhoeae in the mouse model.
Th17 responses have also been detected in humans with
gonorrhoea, and are induced by N gonorrhoeae in human
monocyte-derived dendritic cells along with IL-10. Induction
of the Th17 pathway by N gonorrhoeae is consistent with
other mostly extracellular pathogens that elicit a strong
neutrophil response (reviewed in12).
By contrast with the innate response, the adaptive response
to mucosal N gonorrhoeae infections is poor. Repeated
infections

Supplement
are common and there is no denitive evidence of protective
responses in humans. While partial serotype-specic immunity
was detected in repeatedly infected women in Kenya, there was
no evidence of serotype-specic immunity in less exposed subjects in a rural setting in the USA. The ratio of bactericidal antibodies to antibodies against the reduction-modiable protein
(Rmp), which blocks the bactericidal activity of PorB-specic or
LOS-specic antibodies, has been proposed as a correlate of protection, and in one study, bactericidal antibodies were associated
3
with reduced risk of salpingitis (reviewed in ).

Identication of immunosuppression mechanisms

The lack of knowledge of protective responses against gonorrhoea is a major challenge for gonorrhoea vaccine development.
Appreciation of the immunosuppressive nature of gonorrhoea,
further complicating vaccine development, has been relatively
recent on the time-line of gonorrhoea research beginning with
reports of Opa protein-mediated immunosuppression of T-cell
23
proliferation and induction of B-cell death. The recognition of
several other immunosuppressive mechanisms followed. These
mechanisms include: (1) T-cell-independent polyclonal activation of IgD+CD27+ B cells to produce low-afnity IgM
without inducing a memory response; (2) induction of pyronecrosis in macrophages, which is NLRP3 inammasomedependent and occurs by gonococcal-induced upregulation of
cathepsin B; (3) inhibition of T-cell proliferation due to upregulation of IL-10 and programmed death ligand 1 (PDL-1) in dendritic cells; (4) suppression of Th1- and Th2-driven adaptive
immune responses by mechanisms dependent on TGF- and
IL-10 as well as type 1 regulatory T cells (reviewed in12).
Continued characterisation of the immunosuppressive
mechanisms used by N gonorrhoeae is critical for vaccine development. The bacterial factors responsible for triggering these
pathways should be excluded from a vaccine and understanding
these pathways may identify steps that can be subverted to
induce a protective response. Recently, Russell and colleagues
reported that antibody-mediated neutralisation of TGF- and
IL-10 in mice resulted in Th1-dependent and Th2-dependent
responses and high titre serum and vaginal-specic antibodies.
Moreover, mice also developed a memory response and were
protected against reinfection. Similarly, localised administration
of IL-12 incorporated in sustained-release microspheres induced

Figure 1

Th1-dependent responses, clearance of infection and a protect12

ive memory response (reviewed in ). These studies suggest
that induction of a Th1 response may be the key to inducing
protective immunity against gonorrhoea. This hypothesis was
also proposed by Sparling and colleagues based on protection
studies on mice immunised with viral replicon particles (VRP)
expressing rPorB.3 While it has been assumed that B cells are
most important for vaccine-mediated clearance of N gonorrhoeae, T helper cell responses drive antibody generation and
the immunological memory response and may also be effective
against intracellular gonococci.

FUTURE DIRECTIONS
Immunisation of the genital tract
Currently, the only licenced STI vaccines are against human papilloma virus and, therefore, there are few paradigms for successful vaccination of the genital tract. Understudied areas on
gonorrhoea vaccine research include controlled comparisons of
different immunisation routes used to induce mucosal responses
and the testing of mucosal adjuvants known to enhance immune
24 25
responses in the genital tract.
Other important questions
that are especially relevant to STI vaccines are the potential for
gender-biased responses, and the inuence of coinfection by
other sexually transmitted pathogens on the efcacy of vaccines
against a single pathogen. Little work has been done in this
area.

Application of new vaccine technology

Advances in vaccinology have provided several new approaches
that could be applied to gonorrhoea vaccines. Conventional
approaches to vaccines such as killed/inactivated vaccines,
subunit vaccines, conjugated vaccines, or live, attenuated vaccines, have strived to replicate the type of immunity elicited by
natural infection while disassociating it from a pathogenic event.
Newer approaches to rational vaccine design, which may
include de novo constructs, are directed towards optimisation of
immune responses and/or target delivery. Examples are vectorbased vaccines, which can optimise antigen expression on a
standardised platform that can incorporate multiple antigens.
These platforms could form the basis of the delivery system, or
could be used to increase antigen yield for subsequent purication. Advances in manufacturing and stabilisation include

The product development pathway for a potential gonococcal vaccine.

Supplement
protein-coated microcrystal, nanoparticles, and glassication.
New forms of product delivery could reduce the reliance on
needle-based injection, such as a patch delivery system, microneedles, or orally delivered vaccines.

Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

REFERENCES
Entry into the vaccine pipeline
Each potential product must be evaluated through a product
development pathway that includes preclinical development,
clinical evaluation for safety and efcacy, and manufacturing
scale-up to eventually reach licensure ( gure 1). Many
chal- lenges are inherent in the development process including the
potential timeline of a decade or more and the signicant nal
resources necessary which can be in the billions of dollars. In
the long run, the development of vaccines to prevent infections
has been a signicant public health advance and has proved to
be cost saving or cost effective for many diseases. While it is
unlikely that a gonorrhoea vaccine will be 100% effective, it is
predicted that an efcacy level of 70% would reduce a considerable amount of disease and transmission worldwide. The most
signicant public health impact of a gonorrhoea vaccine would
be on reproductive health. Therefore, a vaccine that protects
against upper reproductive tract infections might be advanced
through the product pipeline, but perhaps not a vaccine that
protects only against urethritis. This rationale is based on a
changing landscape, however, due to the emergence of multiple
drug-resistant gonococcal strains. The potential rise of untreatable gonorrhoea could change the cost benet analysis of a gonorrhoea vaccine as well as the public health message used to
educate the public and providers when a vaccine is introduced.
The case needs to be made for a vaccine to protect against gonococcal infection, because with the growing threat of antimicrobial resistance in N gonorrheae, the time to act may be now.

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Key messages
The impact of gonorrhoea on reproductive health and the
threat of potentially untreatable gonorrhoea support the
need for a gonorrhoea vaccine.
Progress in antigen discovery, gonococcal immunobiology,
and animal modelling, together with the recent success of
meningococcal outer membrane-based vaccines have
reinvigorated gonorrhoea vaccine research.
Further investigation is needed in the areas of mucosal
adjuvants, gender-biased responses, and the impact of
coinfection on vaccine-induced protection.
Entry of gonorrhoea vaccines into the product pipeline will
require a heavy investment of time and money, but the
potential benet should outweigh the risks.

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Handling editor Jackie A Cassell.

Acknowledgements We thank Dr Amanda DeRocco for helpful reading of
the manuscript.
Contributors AEJ and CDD collaborated in the writing of this review. AEJ
contributed sections about the history of gonorrhoea vaccine development and the
current status and technical challenges of research in this area. CDD contributed
the public health perspective on gonorrhoea vaccines, new advances in the eld of
vaccinology, and information pertaining to the product pipeline. Both authors
edited the manuscript before submission.
Funding Funding for this work was provided to AEJ by grant number U19 AI31496
from the National Institute of Health.

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World Health Organization. Global action plan to control the spread and impact of
antimicrobial resistance in Neisseria gonorrhoeae. 2012.
Hook EW, Handseld HH. Gonococcal infections in the adult. In: Holmes KK,
Sparling PF, Mardh P-A, et al. eds. Sexually Transmitted Diseases. New York,
New York: McGraw-Hill, 1999:45166.
Zhu W, Chen CJ, Thomas CE, et al. Vaccines for gonorrhea: can we rise to the
challenge? Front Microbiol 2011;2:12437.
Morand PC, Tattevin P, Eugene E, et al. The adhesive property of the type IV
pilus-associated component PilC1 of pathogenic Neisseria is supported by the
conformational structure of the N-terminal part of the molecule. Mol Microbiol
2001;40:84656.
Haghi F, Peerayeh SN, Siadat SD, et al. Recombinant outer membrane secretin
PilQ (406770) as a vaccine candidate for serogroup B Neisseria meningitidis.
Vaccine
2012;30:171014.
Edwards JL, Brown EJ, Uk-Nham S, et al. A co-operative interaction between
Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary
cervical epithelial cells. Cell Microbiol 2002;4:57184.
Faulstich M, Bottcher JP, Meyer TF, et al. Pilus phase variation switches gonococcal
adherence to invasion by caveolin-1-dependent host cell signaling. PLoS Pathog
2013;9:e1003373.
Falsetta ML, Steichen CT, McEwan AG, et al. The composition and metabolic
phenotype of Neisseria gonorrhoeae biolms. Front Microbiol 2011;2:75.
Clark VL, Knapp JS, Thompson S, et al. Presence of antibodies to the major
anaerobically induced gonococcal outer membrane protein in sera from
patients with gonococcal infections. Microb Pathog 1988;5:38190.
Shewell LK, Ku SC, Schulz BL, et al. Recombinant truncated AniA of pathogenic
Neisseria elicits a non-native immune response and functional blocking antibodies.
Biochem Biophys Res Commun 2013;431:21520.
Hobbs MM, Sparling PF, Cohen MS, et al. Experimental gonococcal infection in
male volunteers: cumulative experience with Neisseria gonorrhoeae strains FA1090
and MS11mkC. Front Microbiol 2011;2:123.
Jerse AE, Bash MC, Russell MW. Vaccines against gonorrhea: current status and
future challenges. Vaccine Published Online First: 6 Sep 2013. doi:10.1016/j.
vaccine.2013.08.067
Pettersson A, Kortekaas J, Weynants VE, et al. Vaccine potential of the
Neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB. Vaccine
2006;
24:354557.
Noinaj N, Cornelissen CN, Buchanan SK. Structural insight into the lactoferrin
receptors from pathogenic Neisseria. J Struct Biol 2013.
Zalucki YM, Cloward JM, Ohneck EA, et al. Function and regulation of Neisseria
gonorrhoeae efux pumps. In: Yu EW, Zhang Q, Brown MH, eds. Microbial Efux
Pumps: Current Research. Horizon Press, Inc, 2013:20223.
Shell DM, Chiles L, Judd RC, et al. The Neisseria lipooligosaccharide-specic
-2,3-sialyltransferase is a surface-exposed outer membrane protein. Infect Immun
2002;70:374451.
Smith H, Parsons NJ, Cole JA. Sialylation of neisserial lipopolysaccharide: a
major inuence on pathogenicity. Microb Pathog 1995;19:36577.
Jerse AE, Wu H, Packiam M, et al. Estradiol-treated female mice as surrogate hosts
for Neisseria gonorrhoeae genital tract infections. Front Microbiol 2011;2:107.
Gulati S, Zheng B, Reed G, et al. Protection against vaginal colonization with
Neisseria gonorrhoeae in mouse model by passive (2C7 mAb) and active
immunizations using a peptide surrogate of the 2C7 LOS epitope. Abstracts of the
18th International Pathogenic Neisseria Conference, Wurzburg, Germany. Abstract
#0118. 2012.
Ngampasutadol J, Rice PA, Walsh MT, et al. Characterization of a peptide vaccine
candidate mimicking an oligosaccharide epitope of Neisseria gonorrhoeae and
resultant immune responses and function. Vaccine 2006;24:15770.
Serruto D, Bottomley MJ, Ram S, et al. The new multicomponent vaccine against
meningococcal serogroup B, 4CMenB: immunological, functional and structural
characterization of the antigens. Vaccine 2012;30(Suppl 2):B8797.
Hadad R, Jacobsson S, Pizza M, et al. Novel meningococcal 4CMenB vaccine
antigensprevalence and polymorphisms of the encoding genes in Neisseria
gonorrhoeae. APMIS 2012;120:75060.
Sadarangani M, Pollard AJ, Gray-Owen SD. Opa proteins and CEACAMs: pathways
of immune engagement for pathogenic Neisseria. FEMS Microbiol Rev
2011;35:498514.
Bode C, Zhao G, Steinhagen F, et al. CpG DNA as a vaccine adjuvant. Expert Rev
Vaccines 2011;10:499511.
Thompson AL, Staats HF. Cytokines: the future of intranasal vaccine adjuvants. Clin
Dev Immunol 2011;2011:289597.
Cole JG, Jerse AE. Functional characterization of antibodies against Neisseria
gonorrhoeae opacity protein loops. PLoS One 2009;4:e8108.

Supplement
27
28
29
30
31

Serino L, Nesta B, Leuzzi R, et al. Identication of a new OmpA-like protein in

Neisseria gonorrhoeae involved in the binding to human epithelial cells and in
vivo colonization. Mol Microbiol 2007;64:1391403.
Price GA, Masri HP, Hollander AM, et al. Gonococcal transferrin binding protein
chimeras induce bactericidal and growth inhibitory antibodies in mice. Vaccine
2007;25:724760.
Cornelissen CN, Hollander A. TonB-dependent transporters expressed by Neisseria
gonorrhoeae. Front Microbiol 2011;2:117.
Stork M, Bos MP, Jongerius I, et al. An outer membrane receptor of Neisseria
meningitidis involved in zinc acquisition with vaccine potential. PLoS Pathog
2010;6:e1000969.
Massari P, Ram S, Macleod H, et al. The role of porins in neisserial
pathogenesis and immunity. Trends Microbiol 2003;11:8793.

32
33

34

35

Gulati S, Agarwal S, Vasudhev S, et al. Properdin is critical for antibody-dependent

bactericidal activity against Neisseria gonorrhoeae that recruit C4b-binding
protein. J Immunol 2012;188:341625.
Keiser PB, Biggs-Cicatelli S, Moran EE, et al. A phase 1 study of a meningococcal
native outer membrane vesicle vaccine made from a group B strain with deleted
lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized
OpcA expression. Vaccine 2011;29:141320.
Zhu P, Klutch MJ, Derrick JP, et al. Identication of opcA gene in
Neisseria polysaccharea: interspecies diversity of Opc protein family. Gene
2003;
307:3140.
Martin D, Cadieux N, Hamel J, et al. Highly conserved Neisseria meningitidis
surface protein confers protection against experimental infection. J Exp Med 1997;
185:117383.

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Vaccine research for gonococcal infections:

where are we?
Ann E Jerse and Carolyn D Deal
Sex Transm Infect 2013 89: iv63-iv68

doi: 10.1136/sextrans-2013-051225
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http://sti.bmj.com/content/89/Suppl_4/iv63

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