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. Author manuscript; available in PMC: 2023 Dec 11.
Published in final edited form as: Antiviral Res. 2020 Jun 13;180:104821. doi: 10.1016/j.antiviral.2020.104821

Use of the guinea pig model of genital herpes to evaluate vaccines and antivirals: review

David I Bernstein 1
PMCID: PMC10713199  NIHMSID: NIHMS1603848  PMID: 32544409

Abstract

Herpes simplex virus (HSV) infections type 1 (HSV-1) and type 2 (HSV-2) are common throughout the world. Infections are lifelong and may produce both acute and recurrent vesiculoulcerative disease as well as more severe diseases. Despite disappointing results from recent HSV vaccine trials new vaccines and more potent antiviral therapies continue to be developed. These newer approaches require initial evaluations in animal models. In this review I have briefly described some of the models available and then more thoroughly describe the guinea pig model of acute and recurrent genital herpes infections. As discussed, the guinea pig model most closely mimics human disease and provides several important endpoints for evaluating vaccines and antivirals.

Introduction

Need for a vaccine and new drugs

Herpes simplex virus (HSV) infections, both type 1 (HSV-1) and type 2 (HSV-2) are among the most common human infections. The worldwide prevalence of HSV-1 infection among 0–49 year olds is estimated to be 67% averaged across all ages. The prevalence increases with age, and is highest in Africa (87% overall prevalence) and lowest in the Americas [1]. Most HSV-1 infections occurred during the first five years of life in Africa and South-East Asia, with virtually no new infection in adulthood.

The worldwide burden of HSV-2 is also high. Among 15–49 year olds, about 417 million (11.7% of the population) are infected [2] .The prevalence is highest in Africa (31.5%) followed by the Americas (14.4%). HSV-2 infections are consistently higher in females (14.8%) compared to males (8.0%) resulting in 267 million women and 150 million men being infected. Both the prevalence and number infected increased with age, especially in the teen years after the onset of sexual activity.

HSV commonly cause self-limited oral and genital vesiculo-ulcerative disease that recurs frequently. However, HSV can also cause more severe disease in neonates and the immunocompromised and is a common cause of encephalitis [3–5]. Further, HSV-2 infections are a significant risk factor for the spread of HIV [6, 7]. In two recent meta-analyses HSV-2 infections were associated with a three-fold increased risk of HIV acquisition. Thus, in areas of high HSV-2 prevalence, a large proportion of HIV infections are attributable to HSV-2.

Because initial HSV infections cause acute primary disease that then persists as latent neural infection which can reactivate to produce recurrent disease or recurrent virus shedding both prophylactic and therapeutic vaccines are needed. Similarly, improved antivirals are needed for both acute and recurrent disease and recurrent virus shedding. The ultimate goal for an HSV prophylactic vaccine would be to totally prevent infection, but such a goal is difficult. Therefore, a vaccine that limits the amount of initial HSV replication and prevents or minimizes the clinical severity of acute disease is a reasonable goal. However, prophylactic vaccines must also limit the amount of virus that reaches potential neural sites of latency during the initial infection, thereby reducing the burden of latent virus and subsequent recurrent disease and recurrent shedding. If a prophylactic vaccine only prevents the symptoms of the initial infection, the result would be a further increase in the number of people unaware of their infection but capable of spreading the disease.

The goals of therapeutic vaccines, i.e. those aimed at patients already infected with HSV, not only include reducing recurrent disease frequency and severity, but also preventing or reducing recurrent shedding during both symptomatic and asymptomatic recurrences. Reduction of shedding is required to impact the spread of HSV as asymptomatic genital shedding is the most important source of virus for transmission [8, 9].

The results of recent trials for prophylactic [10] and therapeutic HSV vaccines [11] have been disappointing and suggest new approaches will be needed. Yet, despite these setbacks, there is continued interest in developing HSV vaccines and thus a need for animal models in which to screen these vaccines. Newer vaccine approaches include, but are not limited to, live attenuated vaccines [12–14] , replication defective vaccines [13, 15, 16] , and multi component glycoprotein [17]. For therapeutic vaccines, the prime and pull approach may be the most interesting new approach [18]. Similarly, new antivirals are being developed [19] which are more effective than current therapies for the treatment of genital HSV-2 infections in guinea pigs [20] and humans [21].

Other, non guinea pig models (Table)

Table 1:

Animal models of genital HSV disease

Species Advantages Disadvantages Primary use
Mouse   1.Inexpensive
  2. Availability of immune reagents		   1. Lethal
  2. No recurrent disease
  3. Requires progesterone pretreatment		   1. Early screen
  2. Investigating immune responses and molecular virology
Rat   1. Inexpensive
  2. May mimic outcome of human trials		   1. Lethal
  2. Limited experience		   1. Early investigations but limited experience with the model
Primate   1. Closest to humans genetically   1. expensive
  2. Does not reliable develop acute or recurrent genital disease		   1. Late investigations
  2. Proof of principle
Guinea Pig   1. Moderate price
  2. Develops scorable primary disease
  3. Develops spontaneous and induced recurrences
  4. Develops recurrent shedding
  5. Can measure burden of latent virus		   1. Failure to predict outcome of human vaccine trials
  2. Limited time of frequent recurrences		   1. Early/Mid investigations
  2. Prophylactic or therapeutic interventions
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Mouse

The most commonly used models for the study of HSV are inbred and outbred mouse models. There are intracerebral, oral facial, corneal, nasal, cutaneous, neonatal, and genital models available [22]. Mice are relatively inexpensive and their use has contributed greatly to our understanding of the molecular biology of acute and persistent infections as well as reactivation events. The major advantage of mouse models is the extensive array of available reagents for the study of immunologic and molecular biologic responses. Further, there are knock out and knock in strains available to allow selective evaluation of gene activity and function.

The outcome of genital challenge is influenced by the age of the mouse, the inbred strain used, the inoculum size as well as the strain of HSV used [22–24]. Thus, results using mouse challenges must be interpreted with these variables in mind. HSV-2 genital challenge usually produces a lethal outcome limiting the utility of these investigations. Further, mouse vaginal challenges require the use of methoxyprogesterone to synchronize the estrus cycle so as to increase susceptibility and decreases immune responses to genital HSV-2 inoculation [25, 26]. Following intravaginal inoculation, animals develop genital disease with erythema and swelling but discrete lesions are not often seen and scoring is more problematic then in guinea pigs [27, 28]. Quantification of local, vaginal, and sometimes neural replication is often included in analysis. Following infection most animals succumb to infection and thus it is not possible to evaluate latent infections, recurrent disease or recurrent virus shedding but it should be noted that thymidine kinase deficient (TK-) virus can be used as a non-lethal murine model [29, 30]. In summary, the mouse model is of most value for defining the local and systemic immune response to infection and identify possible protective responses as well as an inexpensive early screening tool for drugs and vaccines [30–32].

Rat

A lethal cotton rat model of genital disease has also been developed [33]. Four days following medroxyprogesterone treatment cotton rats can be infected intravaginally with both HSV-1 and HSV-2. This model has been used to evaluate the gD vaccine used in the clinical trials. Two doses of vaccine were immunogenic but failed to protect against HSV-2 disease or to decrease genital HSV-2 replication. However, the vaccine significantly reduced vaginal HSV-1 titers and better protected against HSV-1 compared to HSV-2 genital disease. Because these findings are consistent with the large clinical trial [10] there is some interest in this model. However, it is important to note that the study in cotton rats used only 2 doses of vaccine while the clinical trial used 3. This could account for sub optimal protection in the animals.

Non-human primate

Another model developed to test antivirals, vaccines and microbicides is a macaque vaginal HSV-2 infection model [17, 34]. This model has the unique ability to study how HSV-2 infection interacts with HIV [35]. As with Simian-Human Immunodeficiency Virus (SHIV) challenges and mouse genital HSV models, animals are pretreated with medroxyprogesterone 4–5 weeks before intra-vaginal challenge with high doses of HSV-2. Animals then become infected although the development of lesions appears to be low in this model. In one study, only 10% of HSV-2 challenged macaques developed cervical inflammation and/or lesions [29]. However, about 50% of the animals had detectable HSV-2 shedding during a 2-year follow-up, documenting infection. Similar findings were noted in another study where infectious virus and HSV-2 DNA were consistently detected in genital secretions for the first 7 days after inoculation but again clinical signs of infection (lesions or any systemic effects) were not observed. The persistence of latent virus and spontaneous reactivation has also been documented in this model by detection of HSV-2 DNA (102 to 103 copies/swab) from genital swabs collected on days 42 and day 56 after HSV-2 inoculation [36]. As seen in humans, HSV-2 infection also increased the frequency of vaginal SHIV-RT infection [35].

Guinea Pig model

Description of HSV-2 genital model

The main advantages of the HSV-2 genital guinea pig model is that infected animals develop acute self-limited disease that is easily quantifiable and then, most importantly, the animals develop spontaneous clinical recurrences [37–39] that are easily identified (Figure 1). Recurrent lesions may also be induced by UV exposure [40]. Further, infected animals exhibit recurrent shedding in the presence and absence of lesions. Thus, the guinea pig infection mimics the human disease for the key elements of the infection. An added advantage is that, unlike what can be assessed in humans, the animals can be evaluated for the presence and the quantity of acute and persistent neural infection.

Figure 1.

Figure 1

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Genital lesions in the guinea pig model of HSV-2 vaginal infection. A) Severe acute disease occurring on day 6, score 3.5 B) Typical single recurrent lesion.

Evidence of HSV-2 replication in the genital tract of guinea pigs can be detected as early as 12 hr post inoculation in vaginal secretions [34]. In tissues, the highest HSV-2 titers are found initially in the introitus, vagina, and bladder, with lower levels of viral replication occurring in the cervix and uterus but there is no evidence of viremic spread or visceral organ involvement [39]34]. Virus replicating in the introitus and vagina enters sensory nerve fibers within one to two days and ascends to involve the dorsal root ganglia (DRG) and spinal cord. From the DRG and/or the spinal cord, HSV-2 descends back down peripheral nerves to the external genital skin to produce the external genital skin lesions.

Procedures

Female adolescent guinea pigs, usually outbred Hartley strain, weighing about 200–300 grams are inoculated intravaginally by instillation of 0.1 ml of HSV-2 (usually 105-10 pfu6) directly into the vagina after the vaginal closure membrane is opened with pre-moistened calcium alginate swab. A small plastic catheter attached to a syringe is often used. No prior treatment with progesterone is required. Virus induced lesions on the external genital skin (Fig 1) are then scored, most commonly using a scale where: 0, no disease; 1+, redness or swelling; 2 +, a few small vesicles; 3 +, several large vesicles; and 4 +, several large ulcers with maceration[39]. . In addition, animals with lesions intermediate in severity may be assigned scores between the above scores i.e. scores of 0.5, 1.5, 2.5, or 3.5. For clarity, the skin sparsely covered with fine hairs that surrounds and includes the perineum is considered the external genital skin. Severity generally peaks at 5–7 days after challenge and then gradually decline. A declining score is used during this healing stage. Figure 2 shows the typical severity over time.

Figure 2.

Figure 2

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Shows the time course of vaginal virus replication in relation to clinical disease expressed as mean lesion score.

At prescribed times after viral inoculation, vaginal swab samples are obtained to quantify the effect of treatments on the replication of virus in the vagina (Fig 2). Swabs can also be obtained from clinically normal external genital skin or lesions on the external genital skin when they are present. Acute virus shedding usually resolves by days 8–10 so swabs are usually obtained daily or every other day from day 1–10. Swabs are obtained with use of a premoistened calcium alginate swabs which are then placed in tubes with 1.0 ml of minimal essential medium containing 100 units of penicillin, 50 Mg of streptomycin, 50 Mg of gentamicin, and 2.5 Mg of amphotericin B and stored frozen . The viral load in swab specimens can be titered by plaque assay or qPCR.

Recurrent lesions and recurrent viral excretion are then evaluated following recovery from the acute disease ie healing of external genital lesions. Because lesions heal by day 10–14 evaluation for recurrent disease usually begins on day 15. Animals are examined daily for recurrent external lesions (Fig 4) and vaginal swabs obtained for viral shedding from the vagina and external genital skin usually between day 15 and 63–70 days. Recurrent shedding has been noted in the presence and absence of lesions. Shedding may be measured by qPCR to quantitate HSV DNA or by culture to detect infectious virus. PCR is more sensitive but it is unclear what detection means and how it relates to transmissibility.

Figure 4.

Figure 4

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Compares the effect of vaccination on disease when evaluated using the acute disease (the first 2 weeks after challenge) vs. over the entire course of observation (6 weeks, including acute and recurrent disease)

At the conclusion of the experiment animals can be sacrificed and the frequency and quantitation of latent virus load in the DRG and spinal cord examined. Latent virus may be determined by co-cultivation of minced fragments to determine the presence of reactivated virus or quantitated using qPCR to determine the burden of latent HSV DNA [12]. One can also measure the effect of treatment on the initial infection of the DRG by sacrificing animals at about 3–8 days after infection when virus titers are highest in the DRG.

Utility

GPs are the only small animal that can be used for evaluation of both prophylactic and therapeutic vaccines or the treatment of both acute and recurrent disease (Table 1). Further, as indicated above this model allows the evaluation of several key virologic and clinical endpoints for both approaches. When evaluating a prophylactic vaccine or therapy for acute disease the impact on the initial vaginal replication can be measured by obtaining swabs during the first 7–10 days of the infection. During this period, the severity of the acute disease is also evaluated. One would expect a potent intervention to prevent the replication of virus or at least decrease the titer of virus recovered from the vaginal cavity and prevent the development of lesions. We have not evaluated a vaccine that completely prevented initial virus replication i.e. sterilizing immunity.

After recovery from the acute disease animals can be evaluated for recurrent lesions, usually a single vesicle or red lesion, for distinct periods of time or measured as a cumulative score. The frequency of lesions decreases over time so that the typical observation period is about 7–8 weeks after recover from acute disease ie days 15–64 or 71 (Fig 3). Similarly, the effects on recurrent virus shedding can be quantitated by obtaining vaginal virus swabs during the period the animals are observed for recurrent disease. As in humans, shedding can occur in the presence or absence of genital lesions. As recurrent shedding is the most important source for transmission [8, 9] we believe this is a key end point for evaluation of vaccines and other interventions. Similarly, the effects of interventions on the establishment of latent virus is important; reasoning that a potent vaccine or early antiviral interventions would limit virus reaching and replicating in the DRG during the early infection and this reduction would affect subsequent recurrent disease and recurrent virus shedding and thus transmission.

Figure 3.

Figure 3

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Shows the time course for recurrent lesions expressed a mean recurrent lesion scores ( line) as well as the course for recurrent shedding expressed as the per cent of vaginal swabs that are positive for HSV by PCR ( bars)

The evaluation of therapeutic vaccines or interventions aimed at recurrent disease is similar. After recovery from the acute disease, animals are vaccinated usually 2–3 times at specified intervals. Therapeutic vaccines are expected to reduce both recurrent disease and recurrent virus shedding. Similarly antivirals can be initiated during the period of recurrences to impact recurrent disease and recurrent virus shedding [41]. Thus, the procedures are similar to those described above for evaluation of recurrent disease and recurrent virus shedding. Because it is not expected that a therapeutic vaccine will affect the burden of latent virus this evaluation is usually not part of the trial but it can be added.

Other guinea pig models of genital infection

Because HSV-1 has become an important and often the most common cause of genital infections [42] it is important to have a model to evaluate HSV-1 genital infections. Similar to humans, HSV-1 vaginal inoculation of guinea pigs produces lesions that are indistinguishable from HSV-2 and remarkable, like the human infection, recurrences are less frequent following HSV-1 genital infections compared to HSV-2 [43]. This model has been used to evaluate vaccines against both HSV-1 as well as HSV-2 [44]. As in humans the HSV-2 gD vaccine protected against HSV-1 infection and disease. Similarly, as most young adults have been infected with HSV-2 it will be important to study HSV-2 vaccines in the setting of a primary HSV-1 infection. Indeed, such a guinea pig model has been described and used for vaccine evaluations [45].

Of course, genital HSV infections are also common in men. Therefore, a genital HSV-2 model has been developed in male guinea pigs. The original model described inoculation via scarification near the male genitalia [46]. This model produced both acute and recurrent disease. An improvement on this approach using a mucosal, rectal challenge was recently published [47]. Infected animals developed acute and recurrent disease as well as recurrent virus shedding.

Limitations

Despite the large number of clinical and virologic endpoints, the guinea pig model of recurrent HSV disease is limited by the diminishing number of recurrences and recurrent shedding over time. Thus, the observation period is usually limited to 7–8 weeks after recovery from acute disease. This limits the time that therapeutic vaccine can be initiated, usually to 1–2 weeks after recovery from the acute disease and the interval and number of revaccinations, usually 1–2 weeks apart with a maximum of 3 vaccinations.

Until recently the ability to study the immune responses in guinea pigs was also limited but newer reagents now allow the study of HSV specific T cell responses as well as cytokine induction [48, 49]. Using a virus-specific ELISPOT assay in conjunction with cellular proliferation assays, investigators have detected and characterized HSV-specific cell-mediated immune responses present in lymphoid tissues at late time points (8–12 months) after genital HSV-2 infection of guinea pigs. The availability of anti CD4 antibody also allowed examination of the role of CD4 cells in controlling reactivation. When CD4 cells were depleted after establishment of latency by injection of an anti-CD4 monoclonal antibody, the cumulative number of HSV-2 recurrent shedding days and the mean number of days virus was shed were significantly increased in CD4-depleted compared to control-treated animals [50]. Use of new reagents should markedly improve investigation of the immunopathogenesis of disease especially the responses that control reactivation, recurrent disease and recurrent shedding; studies that can only be done in guinea pigs.

A limitation shared by all animal models is the time limitation imposed by the life span of small animals, and the space and cost of housing animals. Thus, prophylactic vaccines are usually provided in weekly to monthly intervals while human vaccines are often spread over 6 months or more to provide optimal immunogenicity. Perhaps, more importantly the animals are challenged at the peak of the immune response (3–4 weeks after the last immunization) whereas humans are evaluated for years after their last immunization. Therefore, it is not surprising that vaccines that provided short term protection in animal models provide little or no protection in clinical trials. In fact, some HSV vaccines appeared to provide short term protection that rapidly waned during clinical trials [51].

When the same criteria used in clinical trials are used to evaluate vaccines in guinea pigs, vaccines that appeared to be protective when assessed using only primary disease were not as effective in the long term [52]. For example, when the definitions for protection used in the recent clinical trial, i.e. assessing lesion development over the entire period of observation, were applied to the evaluation of a live attenuated or a sub unit vaccine in guinea pigs there was a marked reduction in the level of protection (Figure 4). While protection against genital lesions appeared to be high during the acute period of observation, protection over the entire period of observation was low (<30% for either vaccine).

Another difference between animal model and human HSV vaccine evaluations is that animals are challenged only once whereas people are exposed on multiple occasions. This difference has been addressed in the HIV field by using multiple challenges for evaluation of vaccines and antivirals [53–55]. It should be possible to use this approach for HSV.

Summary

Among the many animal models of HSV genital disease, the guinea pig most closely resembles human disease and offers many advantages over other small animal models for the evaluation of drugs, biologics and vaccines (Table 1). Nevertheless, there are limitations to the model that may decrease its predictive value. The endpoints that will best predict success in human trials have yet to be elucidated but it is suggested that at a minimum, only vaccines that protect against acute disease, decrease subsequent recurrences and the burden of latent virus proceed to human evaluations. For therapeutic vaccines, only vaccines that decrease recurrent disease and recurrent shedding should advance.

Supplementary Material

1

Highlights.

Guinea pig model of genital herpes best mimics human disease

Guinea pig model can be used to study effects of drugs and vaccines on acute and recurrent disease.

Endpoints include severity of acute disease, acute virus replication, recurrences, recurrent shedding, and latency

Acknowledgement:

I thank Dr. Christopher J. Harrison, The Children’s Mercy Hospital, Kansas City, Missouri for his careful review and helpful suggestions.

Footnotes

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References

  • 1.Looker KJ, et al. , Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. PLoS One, 2015. 10(10): p. e0140765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Looker KJ, et al. , Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One, 2015. 10(1): p. e114989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Pinninti SG and Kimberlin DW, Neonatal herpes simplex virus infections. Semin Perinatol, 2018. 42(3): p. 168–175. [DOI] [PubMed] [Google Scholar]
  • 4.Gnann JW Jr. and Whitley RJ, Herpes Simplex Encephalitis: an Update. Curr Infect Dis Rep, 2017. 19(3): p. 13. [DOI] [PubMed] [Google Scholar]
  • 5.James SH, Kimberlin DW, and Whitley RJ, Antiviral therapy for herpesvirus central nervous system infections: neonatal herpes simplex virus infection, herpes simplex encephalitis, and congenital cytomegalovirus infection. Antiviral Res, 2009. 83(3): p. 207–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Freeman EE, et al. , Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS, 2006. 20(1): p. 73–83. [DOI] [PubMed] [Google Scholar]
  • 7.Looker KJ, et al. , Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis, 2017. 17(12): p. 1303–1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mertz GJ, Asymptomatic shedding of herpes simplex virus 1 and 2: implications for prevention of transmission. J Infect Dis, 2008. 198(8): p. 1098–100. [DOI] [PubMed] [Google Scholar]
  • 9.Sacks SL, et al. , HSV shedding. Antiviral Res, 2004. 63 Suppl 1: p. S19–26. [DOI] [PubMed] [Google Scholar]
  • 10.Belshe RB, et al. , Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med, 2012. 366(1): p. 34–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bernstein DI, et al. , Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease. Vaccine, 2019. 37(26): p. 3443–3450. [DOI] [PubMed] [Google Scholar]
  • 12.Bernstein DI, et al. , The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes. Vaccine, 2019. 37(1): p. 61–68. [DOI] [PubMed] [Google Scholar]
  • 13.Wang K, et al. , A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2. J Virol, 2016. 90(1): p. 562–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Visalli RJ, et al. , Vaccination with a HSV-2 UL24 mutant induces a protective immune response in murine and guinea pig vaginal infection models. Vaccine, 2014. 32(12): p. 1398–406. [DOI] [PubMed] [Google Scholar]
  • 15.Burn C, et al. , A Herpes Simplex Virus (HSV)-2 Single-Cycle Candidate Vaccine Deleted in Glycoprotein D Protects Male Mice From Lethal Skin Challenge With Clinical Isolates of HSV-1 and HSV-2. J Infect Dis, 2018. 217(5): p. 754–758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Dropulic LK, et al. , A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection. J Infect Dis, 2019. 220(6): p. 990–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Awasthi S, et al. , An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs. PLoS Pathog, 2017. 13(1): p. e1006141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bernstein DI, et al. , Successful application of prime and pull strategy for a therapeutic HSV vaccine. NPJ Vaccines, 2019. 4: p. 33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Birkmann A and Zimmermann H, HSV antivirals - current and future treatment options. Curr Opin Virol, 2016. 18: p. 9–13. [DOI] [PubMed] [Google Scholar]
  • 20.Baumeister J, et al. , Superior efficacy of helicase-primase inhibitor BAY 57–1293 for herpes infection and latency in the guinea pig model of human genital herpes disease. Antivir Chem Chemother, 2007. 18(1): p. 35–48. [DOI] [PubMed] [Google Scholar]
  • 21.Wald A, et al. , Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial. JAMA, 2016. 316(23): p. 24952503. [DOI] [PubMed] [Google Scholar]
  • 22.Kollias CM, et al. , Animal models of herpes simplex virus immunity and pathogenesis. J Neurovirol, 2015. 21(1): p. 8–23. [DOI] [PubMed] [Google Scholar]
  • 23.Ellison AR, et al. , Establishment of latent herpes simplex virus type 1 infection in resistant, sensitive, and immunodeficient mouse strains. Virology, 2000. 268(1): p. 17–28. [DOI] [PubMed] [Google Scholar]
  • 24.Kirchner H, et al. , Differences in susceptibility to herpes simplex virus infection of inbred strains of mice. IARC Sci Publ, 1978(24 Pt 2): p. 783–8. [PubMed] [Google Scholar]
  • 25.Teepe AG, et al. , Effect of the estrous cycle on susceptibility of female mice to intravaginal inoculation of herpes simplex virus type 2 (HSV-2). Antiviral Res, 1990. 14(4–5): p. 227–35. [DOI] [PubMed] [Google Scholar]
  • 26.Kaushic C, et al. , Progesterone increases susceptibility and decreases immune responses to genital herpes infection. J Virol, 2003. 77(8): p. 4558–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Morrison LA, Da Costa XJ, and Knipe DM, Influence of mucosal and parenteral immunization with a replication-defective mutant of HSV-2 on immune responses and protection from genital challenge. Virology, 1998. 243(1): p. 178–87. [DOI] [PubMed] [Google Scholar]
  • 28.Marshak JO, Dong L, and Koelle DM, The Murine Intravaginal HSV-2 Challenge Model for Investigation of DNA Vaccines. Methods Mol Biol, 2020. 2060: p. 429–454. [DOI] [PubMed] [Google Scholar]
  • 29.Diaz FM and Knipe DM, Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus. Virology, 2016. 488: p. 61–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Milligan GN and Bernstein DI, Analysis of herpes simplex virus-specific T cells in the murine female genital tract following genital infection with herpes simplex virus type 2. Virology, 1995. 212(2): p. 481–9. [DOI] [PubMed] [Google Scholar]
  • 31.Parr MB and Parr EL, Vaginal immunity in the HSV-2 mouse model. Int Rev Immunol, 2003. 22(1): p. 43–63. [DOI] [PubMed] [Google Scholar]
  • 32.Shin H and Iwasaki A, Generating protective immunity against genital herpes. Trends Immunol, 2013. 34(10): p. 487–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Boukhvalova M, et al. , Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model. J Virol, 2015. 89(19): p. 9825–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Hsu M, et al. , A combination microbicide gel protects macaques against vaginal simian human immunodeficiency virus-reverse transcriptase infection, but only partially reduces herpes simplex virus-2 infection after a single high-dose cochallenge. AIDS Res Hum Retroviruses, 2014. 30(2): p. 174–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Crostarosa F, et al. , A macaque model to study vaginal HSV-2/immunodeficiency virus coinfection and the impact of HSV-2 on microbicide efficacy. PLoS One, 2009. 4(11): p. e8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Lo M, et al. , Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques. J Virol, 2019. 93(2). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Scriba M, Recurrent genital Herpes simplex virus (HSV) infection of guinea pigs. Med Microbiol Immunol, 1976. 162(3–4): p. 201–8. [DOI] [PubMed] [Google Scholar]
  • 38.Lukas B, Wiesendanger W, and Schmidt-Ruppin KH, Herpes genitalis in guinea-pigs. I. Kinetic study in infection with Herpesvirus hominis type 2. Arch Virol, 1975. 41(1): p. 1–11. [DOI] [PubMed] [Google Scholar]
  • 39.Stanberry LR, et al. , Genital herpes in guinea pigs: pathogenesis of the primary infection and description of recurrent disease. J Infect Dis, 1982. 146(3): p. 397–404. [DOI] [PubMed] [Google Scholar]
  • 40.Stanberry LR, et al. , Recurrent genital herpes in the guinea pig augmented by ultraviolet irradiation: effects of treatment with acyclovir. Antiviral Res, 1990. 13(5): p. 227–35. [DOI] [PubMed] [Google Scholar]
  • 41.Bernstein DI, et al. , Efficacy of N-methanocarbathymidine against genital herpes simplex virus type 2 shedding and infection in guinea pigs. Antivir Chem Chemother, 2015. 24(1): p. 19–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Bernstein DI, et al. , Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis, 2013. 56(3): p. 344–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Landry ML, Myerson D, and Bull C, Recurrent genital infection in the guinea pig: differences between herpes simplex types 1 and 2. Intervirology, 1992. 34(4): p. 169–79. [DOI] [PubMed] [Google Scholar]
  • 44.Bourne N, et al. , Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs. J Infect Dis, 2003. 187(4): p. 542–9. [DOI] [PubMed] [Google Scholar]
  • 45.Hoshino Y, et al. , Protection from herpes simplex virus (HSV)-2 infection with replicationdefective HSV-2 or glycoprotein D2 vaccines in HSV-1-seropositive and HSV-1-seronegative guinea pigs. J Infect Dis, 2009. 200(7): p. 1088–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Stephanopoulos DE, Myers MG, and Bernstein DI, Genital infections due to herpes simplex virus type 2 in male guinea pigs. J Infect Dis, 1989. 159(1): p. 89–95. [DOI] [PubMed] [Google Scholar]
  • 47.Bourne N, et al. , Development of disease and immunity at the genital epithelium following intrarectal inoculation of male guinea pigs with herpes simplex virus type 2. Virology, 2019. 526: p. 180–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Perry CL, et al. , Detection of herpes simplex virus type 2 (HSV-2) -specific cell-mediated immune responses in guinea pigs during latent HSV-2 genital infection. J Immunol Methods, 2016. 439: p. 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Veselenak RL, et al. , Transcriptional Analysis of the Guinea Pig Mucosal Immune Response to Intravaginal Infection with Herpes Simplex Virus Type 2. Virology, 2018. 518: p. 349–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Bourne N, et al. , Increased Frequency of Virus Shedding by Herpes Simplex Virus 2-Infected Guinea Pigs in the Absence of CD4(+) T Lymphocytes. J Virol, 2019. 93(4). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Corey L, et al. , Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA, 1999. 282(4): p. 33140. [DOI] [PubMed] [Google Scholar]
  • 52.Bernstein DI, et al. , Duration of protection from live attenuated vs. sub unit HSV-2 vaccines in the guinea pig model of genital herpes: Reassessing efficacy using endpoints from clinical trials. PLoS One, 2019. 14(3): p. e0213401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Barouch DH, et al. , Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell, 2013. 155(3): p. 531–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Xiao P, et al. , Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge. J Virol, 2012. 86(8): p. 4644–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Subbarao S, et al. , Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. J Infect Dis, 2006. 194(7): p. 904–11. [DOI] [PubMed] [Google Scholar]

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NIHMS1603848-supplement-1.xml (326B, xml)

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