Status of Vaccine Research and Development of Vaccines for Herpes Simplex Virus

Status of Vaccine Research and Development of Vaccines for Herpes Simplex Virus
                                         Prepared for WHO PD-VAC

I. About the Disease and Pathogen
Basic information on pathogen, including transmission, estimated global disease burden for those at risk, for
morbidity and for mortality, including uncertainties/data gaps, geographical distribution, economic burden if
available, age groups affected and target groups for vaccination. Existing preventive, diagnostic and treatment
measures and their limitations.

The Herpes simplex viruses are responsible for a broad-spectrum of diseases affecting all age groups
across the developed and developing world. The viruses are members of the herpesvirus family, which
also includes the human pathogens Varicella-Zoster virus, Epstein-Barr virus, Cytomegalovirus, Human
herpes virus -6 and -8. Herpes simplex virus type -1 (HSV-1) and -2 (HSV-2) are serotypically
differentiated based on genetically different surface glycoproteins, but both types are capable of infecting
the oral or genital mucosa and causing lifelong, incurable infections (1). The virus infects epithelial cells
at skin or mucosal surfaces, and then infects nerve endings, travels up the nerve axon, and establishes
persistent infection in the trigeminal (HSV-1) or lumbosacral (HSV-1 or HSV-2) ganglia, where it is
protected from the host immune response. The virus returns down the axon to cause oral or genital ulcers
or asymptomatic viral shedding. Asymptomatic viral shedding occurs frequently, and during these periods
the virus is transmissible. The ability of the virus to be acquired and transmitted in the absence of
symptoms allows it to spread efficiently and silently throughout the population. As most infections are
subclinical, disease incidence data are thought to underestimate the magnitude of HSV infection.

Although the clinical manifestations of primary infection may be similar between HSV-1 and HSV-2, the
nature of the disease, age groups affected and severity are influenced by the infecting virus type, the
portal of entry, host immune status and whether the infection is initial or recurrent. HSV-1 has been more
traditionally associated with oral-facial infections, although it is now a leading cause of first episode
genital herpes and neonatal herpes in high-income countries (HIC), which is likely related to declining
HSV-1 acquisition during childhood in these settings. Typically universally acquired early in childhood in
lower middle-income countries (LMIC), it causes oral ulcers of varying severity from herpes labialis to
gingivostomatitis and pharyngitis. It is the leading cause of sporadic encephalitis (HSV encephalitis) and
infectious blindness (HSV keratitis) in HIC; the burden of these complications of HSV-1 infection in
LMIC is unknown but likely to be high. Almost universal exposure to HSV-1 appears to be supported by
the high rates of global seroprevalence. More than half of the world’s populations is seropositive for
HSV-1, with over 90% people infected by adolescence in LMIC (2)).

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted infection that is the leading cause of
genital ulcer disease (GUD) worldwide; HSV-2 also causes neonatal herpes and increases the risk of HIV
infection. An estimated 535 million persons are infected with HSV-2 with an incidence of 24 million
infections per year (3). HSV-2 is rapidly acquired among adolescent men and women initiating sexual
activity in settings with high HSV-2 seroprevalence. For instance, in sub-Saharan Africa, the incidence
among women is up to 23 per 100 person years and among men is up to 12 per 100 person years (4).
Neonatal herpes incidence in HIC is ~10 cases/100,000 live births; the incidence in LMIC is unknown.
Although rare, neonatal herpes is associated with high morbidity and mortality and no prevention
strategies have been identified. HSV-2 fuels the HIV epidemic by increasing the risk of HIV acquisition
3-fold through HSV-2 associated genital tract inflammation. In addition, genital ulcer disease increases
the risk of HIV transmission. In settings with high HSV-2 prevalence, 25-50% of HIV infections are
attributable to HSV-2.

Global estimates for the economic burden of HSV infection are not available. In the United States, HSV-
2 infection is estimated to have a total lifetime cost of $540 million US dollars (adjusted to 2010 dollars),

	
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behind only HIV and HPV in costs among 8 major STIs (5). These cost estimates exclude neonatal
herpes, which had a total hospitalization charge of $35 million in 2006 in the United States (6). These
costs also exclude the impact of HSV-2 infection on HIV susceptibility, which would greatly increase
economic burden, especially in high HSV-2 prevalence settings, and complications of HSV-1 infection.
HSV infection will be included in the next iteration of the Global Burden of Disease, which may provide
more precise global estimates.

Although HSV clinical recurrences are commonly self-limited, its numerous complications can be life-
threatening, and consequences life-long, particularly in those with immature or compromised immune
systems. Treatment and control strategies are limited to the antiviral agent, acyclovir and the use of
condoms (~30% efficacy). HSV genital ulcer disease can be treated by acyclovir, which is now included
in WHO guidelines for syndromic management of GUD. Although daily suppressive therapy for HSV-2
infected persons decreases the risk of transmission in discordant partnerships in the US, daily suppressive
antiviral therapy was not effective for prevention of HSV-2 transmission from HIV/HSV-2 coinfected
adults to HSV-2 seronegative partners in the Partners in Prevention study. Breakthrough shedding occurs
despite high dose antiviral therapy; therefore currently available antiviral therapy is unlikely to interrupt
the epidemic. The development of effective vaccines against HSV would address the unmet medical need
of preventing future transmission, with adolescents being the primary target group for preventive HSV-2
vaccination and with HSV-infected populations targeted by therapeutic HSV vaccines, which would
decrease both symptoms and asymptomatic viral shedding. If a vaccine prevented both HSV-1 and HSV-
2 infection, infants would also be a target population.

II. Overview of Current Efforts

       A. Biological feasibility for vaccine development
Evidence that vaccine development is biologically feasible including from development of naturally acquired
immunity, from vaccine development for related pathogens, from animal models or in vitro data

There are no vaccines currently available for HSV infection, but the pipeline is rich with candidates in
various phases of development. Vaccines are being developed both to prevent HSV-2 infection
(preventive) and to treat HSV-2 infection (therapeutic).

There are several lines of evidence that an HSV vaccine is feasible from a biologic standpoint:
   1. There is a safe and efficacious vaccine for varicella zoster virus (VZV), a closely related alpha-
        herpesvirus. Both a live-attenuated vaccine for preventive (prevention of varicella “chicken
        pox”) and therapeutic (prevention of herpes zoster or “shingles”) indications have been
        developed.

       2. Whether protective genital mucosal immunity could be induced by an intramuscular (IM)
          vaccination has been a concerning unknown for the HSV vaccine field. However, the
          development of the human papilloma virus (HPV) vaccine provides ample proof of concept that
          an IM vaccine can be highly efficacious against genital viral pathogens.

       3. The Herpevac trial, which tested a truncated glycoprotein D2 (gD2t) vaccine in >8000 HSV-
          1/HSV-2 seronegative women showed 58% vaccine efficacy for prevention of genital HSV-1
          disease and 32% efficacy for prevention of HSV-1 infection (7). The vaccine did not prevent
          HSV-2 disease or infection. Titers of gD2t were identified as a correlate of protection, based on
          increasing vaccine efficacy with increasing titers of gD2t (8). Further studies showed that sera of
          vaccinees neutralized HSV-1 3-fold better than HSV-2, suggesting that induced titers of gD2
          were sufficient to prevent HSV-1 but not HSV-2 infection. These are the first data suggesting
          that antibody titers are a correlate of anti-HSV-1 immunity and provide a benchmark for inducing
          protective immunity.

	
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HSV-1 and HSV-2 are large DNA viruses that are highly conserved at the amino acid level. The viral
genomes encode for over 80 proteins including numerous surface glycoproteins (targets of humoral
immunity). The recent availability of full-length viral sequences from around the world for both HSV-1
and HSV-2, will allow selection of vaccine targets that could potentially provide protection against both
pathogens, and targets that are not geographically restricted. This, combined with increasing knowledge
regarding the role of neutralizing antibodies and T-cell responses in preventing infection versus
preventing recurrent disease could help improve the design of future candidate vaccines.

       B. General approaches to vaccine development for this disease for low and middle income country
          markets

What are the scientific approaches and indications and target/age/geographic groups being pursued? What public
health needs will these vaccines meet if successfully developed? Where there are several different possible
indications/target groups, how much consensus is there as to prioritization between these for vaccine development
in LMIC.

Two approaches are being pursued for HSV-2 vaccine development: preventive vaccines and therapeutic
vaccines. Preventive vaccines would ideally provide protective immunity against genital HSV-2 infection
prior to exposure, with a possible secondary effect of prevention of HIV infection in high risk
populations. The target population would be adolescent men and women prior to the initiation of sexual
activity. Prior studies of preventive HSV vaccines have focused on HSV-2 discordant couples or HSV-
1/HSV-2 seronegative women in HIC; these studies have been limited by low numbers of study endpoints
(acquisition of genital herpes disease), resulting in large sample sizes and long trials. Preventive vaccines
have not been tested in LMIC. However, the field is moving toward realization that an HSV-2 vaccine
must be effective in LMIC and may be tested in these countries. HSV vaccines that will be effective in
LMIC must be designed to be effective in both HSV-1 seropositive and HSV-1 seronegative persons, and
geographic strain diversity must be accounted for in vaccine design. In addition, testing in LMIC where
HSV-2 is rapidly acquired during adolescence will allow for more efficient trials. If a candidate vaccine
was found to protect against HSV-1 as well as HSV-2 in adolescents, shifting the timing of vaccination to
infant/childhood could also be considered. Such a vaccine may also prevent HSV-1 related eye and
neurologic disease. Many of these and other related considerations do not have clear consensus in the
field.

Therapeutic vaccines are being tested in HSV-2 seropositive persons to reduce genital lesions and genital
shedding, which may provide both personal and public health benefit. The target population is persons
who have already acquired genital HSV-2 infection. Initial studies of 2 candidate vaccines have shown
positive results. These vaccines are being tested in HIC at this time, and there is no consensus to
prioritizing therapeutic vaccines in LMIC. A potential issue that will need to be addressed is whether the
therapeutic vaccines result in increased genital inflammation as additional T-cells traffic to the genital
tract, which may further increase the risk of acquiring HIV.

III. Technical and Regulatory Assessment
Highlight perceived positive/negative aspects in clinical/regulatory pathways e.g. well established product
development and regulatory pathway to licensure, accepted immune correlates and/or functional assays, accepted
surrogate efficacy endpoints, existence of well accepted animal or challenge models, agreed trial designs and
endpoints. Possibilities to develop case for correlates/surrogates should be included.

Preclinical development of HSV vaccines utilizes well-established animal models to test and screen
promising candidate vaccines. The mouse model presents a well-developed model of genital infection and
is convenient but does not recapitulate human infection as genital reactivation does not occur, and
mortality is high in initial infection. The guinea pig model is a well-established model of genital HSV-2

	
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infection that mimics infection in humans and that is used to test candidate vaccines. However,
promising vaccines in the guinea pig model have not translated to efficacy in humans. There is often a
long delay in testing promising preclinical candidates in clinical trials.

The clinical pathways to licensure and implementation for an adolescent vaccine have been well
established through the HPV vaccine. Identified challenges include effective marketing of a vaccine to
prevent an STI, which the HPV vaccine was able to circumvent to a certain degree through marketing the
vaccine as cancer prevention.

There are no accepted immune correlates of protection, although the recent finding of an immune
correlate for protection of genital HSV-1 infection is promising (8). In infected persons, genital shedding
is becoming more accepted as a biomarker for efficacy of therapeutic vaccines.

For preventive vaccines, there is no consensus on designs or endpoints, but in the wake of the Herpevac
trial, there is growing interest in use of HSV-2 infection (seroconversion) as an endpoint rather than HSV-
2 disease (clinically recognized genital ulcer syndrome). In addition, we have learned that large phase III
vaccine trials must be performed in populations with substantial HSV-2 incidence.

IV. Status of vaccine R&D activities
Summarize status of vaccine design, pre-clinical and clinical trial activity, including platforms, vectors, and
adjuvants. Note academic, government, biotech and industry entities engaged. Summarize antigenic targets (if
subunit approaches). Section on major advances in last 3-5 years, including key opportunities highlighted by recent
science developments in the area.

Multiple vaccine candidates with diverse platforms have been studied in the preclinical phase and several
are being tested in clinical trials, with early development supported mainly by academic institutions,
government, and biotech companies. Several pharmaceutical companies have also been involved with
testing HSV vaccines, including Sanofi Pasteur and GlaxoSmithKline.

The most widely used approach in human clinical trials has been glycoprotein subunit vaccines.
Glycoproteins are expressed on the viral surface and induce neutralizing antibodies and therefore are a
rational target. The largest clinical trials to date include the Herpevac trial, which used glycoprotein D-2
(gD2) with alum/MPL adjuvant (7) and the Chiron HSV Vaccine using glycoprotein gB2/gD2 with MF59
adjuvant (9). Although the Herpevac trial did not show efficacy against HSV-2 disease, the findings that
HSV-1 infection could be prevented and that there is an immune correlate of protection is a significant
advance for the HSV field and provides proof of concept that mucosal immunity can be stimulated
through vaccination and that genital infection can be prevented; second generation preventive vaccines
may need to stimulate higher titers of neutralizing antibody.

Glycoprotein candidates with novel platforms are still being explored. For instance, a gD/gC/gE subunit
glycoprotein candidate is promising in mice (10). Novel delivery methods of glycoprotein including
lentiviral vectors expressing glycoprotein B and intranasal delivery are being explored. There are several
live-attenuated or replication-incompetent virus vaccine candidates in the preclinical phase. A
replication-incompetent HSV-2 vaccine (HSV529) has entered Phase I trials for both preventive and
therapeutic indications.

Within the past 2 years, 4 additional candidates have entered into Phase I/II trials as therapeutic vaccines.
These vaccine candidates have novel adjuvants, which stimulate T-cell immunity. Preliminary results
were reported for GEN-003, a gD/ICP4 protein subunit vaccine with Matrix M adjuvant, with ~50%
decline in genital HSV shedding rate after the therapeutic vaccine series . Preliminary results from a
Phase II study of HerpV, a 32 peptide vaccine linked to HSP and QS-21 adjuvant, showed a 15% decrease

	
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in shedding after the initial vaccine series. A DNA vaccine with gD/UL46/UL47, adjuvanted with
Vaxfectin® has also entering Phase I trials for a therapeutic indication.

The realization that genital HSV infection induces tissue resident memory T cells has been a major recent
advance in the field. Animal studies have demonstrated the importance of stimulating tissue resident
memory T-cells for prevention of HSV infection in the mouse model using a “prime and pull” approach,
in which a topical chemokine applied to the genital mucosa after subcutaneous vaccination drew HSV
specific CD8+ T cells and was associated with decreased clinical disease upon challenge with HSV-2
(11). While this approach has not entered clinical trials, it is an innovative and highlights the importance
of tissue resident T cells in the genital tract.

Table 1: Development Status of Current Vaccine Candidates (POC = Proof of concept trial)

Candidate Name/Identifier                   Preclinical      Phase I     Phase II      POC        Phase III
GEN-003 (gD2/ICP4/MM adjuvant)                                             X            X
HerpV (32 35-mer peptides, HSP                                             X            X
adjuvant
Coridon (gD2 codon                                             X
optimized/ubiquitin-tagged)
VCL-HB01                                                       X
(gD2/UL46/UL47/Vaxfectin)
HSV529 (HSV-2 mutated for                                      X
UL5/UL29)
Herpevac (gD2/MPL/alum)                                                                               X
gD/gC/gE (Trivalent glycoprotein)               X
0ΔNLSICP0 live attenuated                       X
HF10 (HSV-1 mutated for UL43,                   X
UL49.5, UL55, UL56, LAT)
AD472 (HSV-2 mutated for g34.5,                 X
UL43.5, UL55-56, US10, US11, US12)
CJ-2-gD2 HSV-2 gD dominant neg                  X
HSV-2 mutated for TK, prime/pull                X
Inactivated HSV-2 in MPL/alum                   X
HSV-1 glycoprotein B lentiviral vector          X
Recombinant HSV-1 gB intranasal                 X

	
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References

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6.     Flagg EW, Weinstock H. Incidence of Neonatal Herpes Simplex Virus Infections in the United
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7.     Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, et al. Efficacy results of a
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8.     Belshe RB, Heineman TC, Bernstein DI, Bellamy AR, Ewell M, van der Most R, et al. Correlate
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9.     Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Douglas JM, Jr., et al. Recombinant
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       trials. Chiron HSV Vaccine Study Group. Jama. 1999;282(4):331-40.
10.    Awasthi S, Huang J, Shaw C, Friedman HM. Blocking Herpes Simplex Virus 2 Glycoprotein E
       Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine
       for Genital Herpes. Journal of Virology. 2014;88(15):8421-32.
11.    Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local
       memory T cells. Nature. 2012;491(7424):463-7.

	
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