Abstract
Background
The incidence of herpes zoster (HZ) has increased in the United States concurrent with decrease in herpes simplex virus (HSV) prevalence. We hypothesized that lack of HSV-elicited cross-reactive immunity to varicella-zoster virus (VZV) results in an increased risk of HZ. Using specimens from the placebo arm of the Shingles Prevention Study, we investigated whether persons who develop HZ are less likely to have prior HSV infection than persons who do not develop HZ, and whether HZ is less severe in persons with HSV than in HSV seronegative persons.
Methods
We conducted a nested case-control (1:2) study comparing the seroprevalence of HSV-1 and HSV-2 in cases (persons with polymerase chain reaction-confirmed HZ) to age-, sex-, and health-matched controls (persons without HZ).
Results
Sera from 639 study participants (213 cases and 426 controls) yielded definitive HSV antibody results and were analyzed. Overall, HSV seropositivity rate was 75%. HSV seronegativity was significantly higher in HZ cases than controls (30.5% vs 22.3%; P = .024), with a 55% higher risk of HZ in HSV seronegative than HSV seropositive participants. HSV seropositivity was associated with more severe HZ (P = .021).
Conclusions
Our study demonstrated that prior infection with HSV partly protects against HZ.
Keywords: herpes simplex virus, herpes zoster, T-cell cross-reactivity, varicella-zoster virus
This case-control study, which compared seroprevalence of herpes simplex virus (HSV) in persons with herpes zoster (HZ) to controls without HZ, showed that HSV seronegativity was significantly higher among HZ cases than controls, indicating that HSV infection protects against HZ.
Primary infection with varicella-zoster virus (VZV) results in varicella (chickenpox), during which VZV establishes latency in sensory and autonomic ganglia [1]. VZV may subsequently reactivate to cause herpes zoster (HZ), or shingles, a localized disease of the sensory ganglion, nerve, and skin that manifests as a painful dermatomal rash. The incidence of HZ increases markedly with increasing age, and this results in high morbidity and cost of medical care [2]. The lifetime risk of HZ in an unvaccinated population is approximately 30% [3, 4]. As people age, the incidence of HZ increases in association with an age-dependent decline in cell-mediated immunity (CMI) to VZV. HZ also occurs more frequently in immunocompromised persons, including persons with immune-mediated diseases and persons receiving immunosuppressive therapies [2]. Postherpetic neuralgia (PHN), which is characterized by the onset or persistence of neuropathic pain and dysesthesia after the HZ rash has healed, is the most common debilitating complication of HZ. It occurs in approximately 21% of persons with HZ who are ≥50 years of age [5]. More than 30% of persons with PHN have neuropathic pain for >1 year [5]. The development of PHN is associated with older age and with greater severity of pain at the onset of HZ [5].
Several studies, conducted in a variety of older adults in the United States, have noted an increase in the age-adjusted incidence of HZ in the last decades [3, 6–9]. In one recent analysis, the age-adjusted incidence of HZ increased from 2.5 per 1000 in 1993 to 7.2 per 1000 in 2016, an almost 3-fold increase [9]. Similarly, a systematic review and meta-analysis of global studies of HZ revealed that the cumulative incidence of HZ in older adults has increased over time in countries in Asia, Oceania, North America, and Europe [10, 11]. The increase in the age-adjusted incidence of HZ does not appear to be fully attributable to changes in health care seeking behavior, increases in case ascertainment, the use of immunosuppressive agents, and/or the prevalence of chronic comorbidities [2, 9, 12]. Another potential explanation for the observed increase in HZ is the introduction of childhood varicella vaccination, which has reduced the burden of childhood varicella by approximately 90% since 1995 and decreased the exposure of adults to VZV [13]. Consequently, VZV-specific CMI, important for preventing VZV reactivation and replication resulting in HZ, may wane in the absence of periodic re-exposure to VZV (ie, exogenous boosting) [14, 15]. However, recent studies have demonstrated that the correlation between the increased incidence of HZ and childhood varicella vaccination coverage is poor [8, 16], and several studies suggest that the incidence of HZ rose prior to implementation of childhood varicella vaccination [8, 12, 17–19].
In contrast to the incidence of HZ, the age-adjusted prevalence of herpes simplex virus (HSV) infection in the United States has decreased in recent decades [20]. Temporal trends in HSV seroprevalence in the United States since the 1970s have been well documented by the Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES) [21–24]. The age-adjusted prevalence of HSV type 1 (HSV-1) declined from 66.4% in 1976–1980 [22] to 48.1% in 2015–2016 [23]. Similarly, the age-adjusted prevalence of HSV type 2 (HSV-2) decreased from 16.0% [21] to 12.1% [23] during the same time period. Consequently, a higher proportion of adults now enter later life without having HSV-elicited immune responses.
HSV-1 and HSV-2 are alphaherpesviruses with broad genetic homology to VZV. Like VZV, they establish latent infections of neurons in the sensory ganglia, from which they can reactivate to cause disease. Of the ≥71 protein coding genes in VZV [25], all but 6 have homologs in HSV [26], and most of the proteins encoded by HSV and VZV have conserved domains with amino acid sequence homologies. To date, 15 VZV-HSV cross-reactive T-cell epitopes have been identified [27–29] but, given the complexity of the T-cell response to these viruses [30, 31] and data from whole-virus–based assays [27], it is likely that there are many more. Approximately 30% of HSV-1–reactive CD8 T cells cross-react with VZV, while the level of cross-reactive CD4 T cells ranges from 20% to 80% [27].
We hypothesized that a decrease in HSV prevalence results in an increased risk of HZ because of a lack of cross-reactive immunity. To determine whether HSV infection affects the risk of HZ, we utilized archival sera and data from the placebo arm of the Shingles Prevention Study (SPS), the clinical trial that demonstrated that live-attenuated Oka/Merck zoster vaccine (zoster vaccine live [ZVL]; Zostavax) reduced the risk and severity of HZ in older adults [32]. We investigated (1) whether persons with prior HSV infection are less likely to develop HZ; and (2) whether, in persons who develop HZ, the disease is less severe in persons previously infected with HSV than in HSV seronegative persons.
METHODS
Study Design
We conducted a nested case-control (1:2) study to compare the seroprevalence of HSV-1 and HSV-2 in cases (persons with polymerase chain reaction [PCR]-confirmed HZ) and controls (persons without HZ) in the placebo arm of the SPS [32]. During a mean follow-up of 3.13 years (median 3.12 years), 981 SPS participants developed HZ, including 660 placebo recipients. The primary exposure of interest in our analysis was seropositivity for HSV-1 and/or HSV-2 in cases versus controls. The study also aimed to determine whether HZ was less severe among participants with prior HSV infection than in HSV seronegative participants. Because >95% of SPS participants were white, and race may contribute to the risk of HZ [2, 33], our study was restricted to specimens and data from white SPS placebo recipients. All participants were immunocompetent at enrollment into the SPS. Participants who were immunosuppressed at HZ onset and those with more than 1 episode of HZ were excluded; participants with HZ-like rashes that were proven not to be HZ were also excluded.
Serum Specimens
Serum specimens were collected during follow-up from suspected cases of HZ in the SPS [32]. Sera from controls were from participants enrolled concurrently into the SPS and an immunology substudy [34] who did not develop HZ during the SPS. Sera were stored frozen below −75°C.
Power Calculations and Statistical Analysis
We assumed that 75% of SPS participants were HSV seropositive, in accordance with a contemporaneous national survey [24]. We calculated that 200 cases and 400 matched controls would provide >80% power to detect an association between the occurrence of HZ and HSV seronegativity, with an odds ratio (OR) of ≥1.8. A total of 220 cases and 440 controls were selected (men to women, 1:1), including a 10% excess to compensate for possible indeterminate HSV serology results. Controls were matched by age (± 5 years) at enrollment in the SPS, sex (self-reported), and health status at enrollment. Health status was measured by the European quality of life (EuroQol) instrument, a visual-analog scale [35], which was provided to SPS participants to rate their general health status from 0 (worst imaginable health) to 100 (best imaginable health) [32]. Controls were health-matched to cases within 10 points of the EuroQol score.
To evaluate the end point of severity of HZ, case selection was weighted towards cases with PHN and high pain scores. During the SPS, HZ-associated pain severity was measured repeatedly on a 0 (no pain) to 10 (worst pain imaginable) Likert scale using the validated Zoster Brief Pain Inventory [36]. The HZ severity-of-illness score was defined as the area under the curve of HZ-associated pain severity plotted against time during the 182-day follow-up period after HZ rash onset [32]. PHN was defined as HZ-associated pain rated as 3 or greater, that persisted or appeared more than 90 days after HZ rash onset [32]. All relevant data associated with the cases and controls were extracted from the de-identified SPS study database.
To evaluate potential change in the odds of HZ occurrence due to HSV serostatus, conditional logistic regression analysis was performed, using HZ as the outcome and HSV serostatus, as well as the matching variables age (± 5 years), sex, and general health status (EuroQol score ± 10 points) as predictors. Univariate and multivariate statistical analyses were applied to examine the relationships between incidence of HZ and these variables, and to examine possible confounding factors. The potential effect of HSV serostatus on HZ severity was assessed using linear regression with the outcome of HZ severity, measured by the HZ severity-of-illness score [32]. Because the distribution of HZ severity-of-illness scores was non-normal, we applied log2 transformation to reduce right skewness and achieve near normal distribution of the data. Linear regression analyses were performed using log2 transformed HZ severity-of-illness scores. Potential confounders that might influence the outcome included HSV serostatus, age, sex, and health status at time of SPS enrollment. Pain scores of HSV seronegative versus HSV seropositive cases were graphed prior to analysis to determine if the distribution of HZ severity-of-illness scores was normal. Statistical analyses were conducted in SPSS version 19 (IBM Corp.) and R Statistical Software, version 4.1.0. Two-sided P value ≤.05 was considered statistically significant.
HSV Type-Specific Serology
Serum aliquots (500 µL each) were tested at the University of Washington (UW) Clinical Virology Laboratory for immunoglobulin G (IgG) antibody to HSV-1 and HSV-2 by Western blot (WB) assay as described previously [37]. The laboratory personnel and UW investigators (A.W., D.M.K., K.F.L., S.S.) remained blinded to assignment and to associated data for the samples until all WB results were obtained and validated. Samples that yielded an indeterminate result for one HSV serotype and were negative for the other serotype were excluded, as detailed in the “Results” section.
Human Subjects
The US Department of Veterans Affairs San Diego Healthcare System Institutional Review Board reviewed this study prior to its initiation and determined the research to be exempt under US Department of Health and Human Services category 4.
RESULTS
Of the 660 sera submitted for HSV-specific IgG detection by WB assay, 653 (98.9%) yielded unequivocal HSV serotype results. The remaining 7 samples (3 cases, 4 controls), which were seronegative for HSV-1 and indeterminate for HSV-2, were excluded from analyses, as the donors could not be confidently categorized with respect to HSV infection. The 2 matched samples associated with each of these indeterminate sera were also excluded.
The final study population consisted of 639 participants, 49.8% men, with a median age of 68 years (range 60 to 84) at SPS enrollment (Table 1). General health status at SPS enrollment, measured by EuroQol, ranged from 43 to 100 (median, 90; mean, 87.4).
Table 1.
Demographics and Distribution of HSV Serotypes of Study Participants
| Cases (n = 213) | Controls (n = 426) | Total (n = 639) | |
|---|---|---|---|
| Age, y | |||
| Median (IQR) | 68 (63–74) | 68 (63–74) | 68 (63–74) |
| Mean | 68.89 | 68.70 | 68.76 |
| Sex | |||
| Men | 106 (49.8) | 212 (49.8) | 318 (49.8) |
| Women | 107 (50.2) | 214 (50.2) | 321 (50.2) |
| EuroQol | |||
| Median (IQR) | 90 (80–95) | 90 (81–95) | 90 (80–95) |
| Mean | 86.69 | 87.81 | 87.44 |
| HSV antibody status | |||
| Seronegative | 65 (30.5) | 95 (22.3) | 160 (25.0) |
| Men | 41 (63.1) | 53 (55.8) | 94 (58.8) |
| Women | 24 (36.9) | 42 (44.2) | 66 (41.3) |
| HSV seropositive | 148 (69.5) | 331 (77.7) | 479 (75.0) |
| Men | 65 (43.9) | 159 (48.0) | 224 (46.8) |
| Women | 83 (56.1) | 172 (52.0) | 255 (53.2) |
| HSV-1 positive only | 120 (56.3) | 263 (61.7) | 383 (59.9) |
| Men | 53 (44.2) | 130 (49.4) | 183 (47.8) |
| Women | 67 (55.8) | 133 (50.6) | 200 (52.2) |
| HSV-2 positive only | 6 (2.8) | 16 (3.8) | 22 (3.4) |
| Men | 4 (66.7) | 5 (31.3) | 9 (40.9) |
| Women | 2 (33.3) | 11 (68.7) | 13 (59.1) |
| HSV-1 and HSV-2 positive | 16 (7.5) | 38 (8.9) | 54 (8.5) |
| Men | 6 (37.5) | 14 (36.8) | 20 (37.0) |
| Women | 10 (62.5) | 24 (63.2) | 34 (63.0) |
| HSV-1 positive, HSV-2 indeterminate | 6 (2.8) | 14 (3.3) | 20 (3.1) |
| Men | 2 (33.3) | 10 (71.4) | 12 (60.0) |
| Women | 4 (66.7) | 4 (28.6) | 8 (40.0) |
Data are No. (%) except where indicated.
Abbreviations: EuroQol, European quality of life instrument; HSV, herpes simplex virus; IQR, interquartile range; y, years.
Seroprevalence of HSV in the Study Population
Overall seropositivity for HSV was 75%, with 59.9% seropositive for HSV-1 only, 3.4% seropositive for HSV-2 only, 8.5% seropositive for both HSV-1 and HSV-2, and 3.1% positive for HSV-1 and indeterminate for HSV-2 (Table 1). More men (29.6%) than women (20.6%) were HSV seronegative. Sera from 20 persons (6 cases, 14 controls) were seropositive for HSV-1 but indeterminate for HSV-2. The serotyping results for these 20 samples and their matched case or control sera were included in the overall HSV analyses but were excluded from the type-specific analyses.
Seroprevalence of HSV in Persons with HZ Versus Controls
HSV seronegativity was significantly higher among cases of HZ than controls (30.5% vs 22.3%; OR, 1.55; 95% confidence interval [CI], 1.06–2.26; P = .024; Table 2). Older age and worse health status were also significantly associated with the risk of HZ. In multivariate analyses, the estimates of magnitude of association between HSV serostatus and the risk of HZ did not change substantially.
Table 2.
Association of Age, Health Status (EuroQol), and HSV Serostatus With Incidence of Herpes Zoster
| Univariate Analysis | Multivariate Analysis | |||||
|---|---|---|---|---|---|---|
| Cases (n = 213) | Controls (n = 426) | OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Age, y, median (IQR) | 68 (63–74) | 68 (63–74) | 1.63 (1.19–2.24) | .002 | 1.65 (1.20–2.28) | .002 |
| Men | 69 (63–75) | 68 (63–75) | 2.95 (1.40–6.20) | .004 | 3.00 (1.32–6.83) | .009 |
| Women | 68 (63–73) | 68 (63–72) | 1.35 (.97–1.87) | .073 | 1.39 (1.00–1.94) | .050 |
| EuroQol, median (IQR) | 90 (80–95) | 90 (81–95) | 0.91 (.87–.96) | <.001 | 0.91 (.86–.95) | <.001 |
| Men | 90 (80–95) | 90 (80–95) | 0.86 (.78–.94) | .001 | 0.85 (.77–.93) | .001 |
| Women | 90 (80–95) | 90 (85–95) | 0.94 (.88–1.00) | .050 | 0.94 (.88–.99) | .031 |
| HSV seronegative, No. (%) | 65 (30.5) | 95 (22.3) | 1.55 (1.06–2.26) | .024 | 1.54 (1.05–2.26) | .028 |
| Men | 41 (63.1) | 53 (55.8) | 1.97 (1.17–3.34) | .011 | 2.24 (1.29–3.89) | .004 |
| Women | 24 (36.9) | 42 (44.2) | 1.18 (.68–2.06) | .564 | 1.09 (.62–1.93) | .757 |
Statistically significant results are bolded.
Abbreviations: CI, confidence interval; EuroQol, European quality of life instrument; HSV, herpes simplex virus; IQR, interquartile range; OR, odds ratio; y, years.
Next, we limited the analysis to the subset of cases and controls that were either seropositive for HSV-1 only or HSV seronegative (130 cases, 260 matched controls). Similar to the overall findings, HSV seronegativity was significantly higher among cases than controls (34.6% vs 23.8%; OR, 1.72; 95% CI, 1.07–2.76; P = .024; Table 3). Because the number of persons who were HSV-2 seropositive was small, we did not analyze the effect of HSV-2 serostatus on the risk of HZ.
Table 3.
Association of Age, Health Status (EuroQol), and HSV-1 Serostatus With Incidence of Herpes Zostera
| Univariate Analysis | Multivariate Analysis | |||||
|---|---|---|---|---|---|---|
| Cases (n = 130) | Controls (n = 260) | OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Age, y, median (IQR) | 69 (64–74) | 69 (64–74) | 1.85 (1.08–3.16) | .024 | 1.80 (1.04–3.11) | .035 |
| EuroQol, median (IQR) | 90 (80–95) | 90 (85–95) | 0.93 (.88–.99) | .021 | 0.93 (.87–.99) | .017 |
| HSV seronegative, No. (%) | 45 (34.6) | 62 (23.8) | 1.72 (1.07–2.76) | .024 | 1.70 (1.05–2.74) | .030 |
Statistically significant results are bolded.
Abbreviations: CI, confidence interval; EuroQol, European quality of life instrument; HSV, herpes simplex virus; IQR, interquartile range; OR, odds ratio; y, years.
aOnly matching cases and controls that were either seronegative or positive for HSV-1 alone were used in the analysis.
Severity of HZ in HSV Seropositive and Seronegative Cases
The severity of HZ among cases was determined by the HZ severity-of-illness score, with log2 transformed scores ranging from 0 to 10.82 (median = 7.52; mean = 7.14; Figure 1). The distribution of pain scores by HSV serostatus is summarized in Table 4.
Figure 1.
Distribution of HZ severity-of-illness scores in 213 cases. A, Distribution of HZ severity-of-illness scores in cases. The histogram shows that distribution of the HZ severity-of-illness scores is non-normal, with the majority of cases having low pain scores, ranging from 0 to 600. B, Distribution of log2 transformed HZ severity-of-illness scores among HSV seronegative and HSV seropositive cases. Abbreviations: HSV, herpes simplex virus; HZ, herpes zoster; HZ severity-of-illness score (area under the curve of HZ-associated pain severity plotted against time during 182 days of follow-up); SD, standard deviation.
Table 4.
Distribution of HZ Severity-of-Illness Scores by HSV Serostatus
| HSV Seronegative (n = 65) | HSV Seropositive (n = 148) | Total (n = 213) | t Test 2-Tailed | |
|---|---|---|---|---|
| HZ SOI score, median (IQR) | 156 (30.50–407.50) | 198 (98.75–383.63) | 182 (79.00–391.50) | |
| HZ SOI score, mean | 286.37 | 301.09 | 296.60 | .763 |
| Log2 HZ SOI score, median (IQR) | 7.29 (4.98–8.67) | 7.63 (6.64–8.59) | 7.52 (6.32–8.61) | |
| Log2 HZ SOI score, mean | 6.61 | 7.37 | 7.14 | .022 |
Statistically significant results are bolded. Abbreviations: HSV, herpes simplex virus; HZ, herpes zoster; HZ SOI score, HZ severity-of-illness score (area under the curve of HZ-associated pain severity plotted against time during 182 days of follow-up); IQR, interquartile range.
In univariate analysis, higher age, lower health (EuroQol) scores, and prior HSV infection correlated with higher log2 HZ severity-of-illness scores. In univariate analysis, the HZ severity-of-illness score increased by 8% for each 1-year increase in age (Table 5). HZ severity increased by 2% with each 1-point decrease on the EuroQol scale (Table 5). HSV seropositive participants had, on average, 69% higher HZ severity-of-illness scores than HSV negative persons (Table 5), suggesting that HSV infection may not reduce the severity of HZ. In a multivariate model of HZ severity, both increase in age (8%) and HSV infection (61%) were associated with higher HZ severity-of-illness scores (Table 5).
Table 5.
Effect of Sex, Age, Health Status, and HSV Serostatus on HZ Severity Using Log2 HZ Severity-of-Illness Scores, n = 213 (106 Men, 107 Women)
| Univariate Regression Analysis | Multivariate Regression Analysis | |||||
|---|---|---|---|---|---|---|
| Variable | β | Percent Change (95% CI) | P Value | β | Percent Change (95% CI) | P Value |
| Sex, women | −0.21 | −13 (−43 to 32) | .503 | −0.19 | −12 (−41 to 31) | .520 |
| Age | 0.12 | 8 (5 to 12) | <.001 | 0.11 | 8 (4 to11) | <.001 |
| Men | 0.15 | 11 (6 to 16) | <.001 | 0.13 | 10 (5 to 15) | <.001 |
| Women | 0.08 | 6 (1 to 11) | .016 | 0.08 | 6 (1 to11) | .017 |
| EuroQol | −0.04 | −2 (−4 to 0) | .021 | −0.02 | −1 (−3 to 1) | .139 |
| Men | −0.05 | −3 (−6 to 0) | .038 | −0.02 | −1 (−4 to 2) | .397 |
| Women | −0.02 | −1 (−4 to 1) | .301 | −0.02 | −1 (−4 to 1) | .294 |
| HSV seropositivity | 0.76 | 69 (8 to 165) | .022 | 0.69 | 61 (4 to 148) | .033 |
| Men | 1.01 | 101 (5 to 284) | .034 | 0.71 | 64 (−12 to 206) | .122 |
| Women | 0.57 | 49 (−22 to 185) | .229 | 0.62 | 54 (−19 to 191) | .183 |
Statistically significant results are bolded. The β coefficient indicates the average amount by which the log2 HZ severity-of-illness score increases when the examined variable increases by one unit or changes in reference to the default reference category. Percent change was calculated by exponentiating the β coefficient with base 2.
Abbreviations: CI, confidence interval; EuroQol, European quality of life instrument; HSV, herpes simplex virus; HZ, herpes zoster.
We obtained HSV serotyping results for 62 of the 63 selected cases with PHN (40 men, 22 women). While a higher percentage of HSV seronegative than HSV seropositive cases experienced PHN, this difference was not statistically significant (Table 6).
Table 6.
Distribution of Postherpetic Neuralgia by HSV Serostatus in 213 Cases
| HSV Seronegative (n = 65) | HSV Seropositive (n = 148) | Total (n = 213) | χ2 (1; n = 213) | P Value | |
|---|---|---|---|---|---|
| PHN, No. (%) | 22 (33.8) | 40 (27.0) | 62 (29.1) | 1.02 | .313 |
| No PHN, No. (%) | 43 (66.2) | 108 (73.0) | 151 (70.9) |
Abbreviations: HSV, herpes simplex virus; PHN, postherpetic neuralgia.
Impact of Sex on HZ Incidence and Severity
When stratified by sex, health status had a significant effect on HZ incidence in both sexes (Table 2). In addition, HSV seronegativity and older age were both significantly associated with HZ incidence in men but not in women (Table 2). In univariate analysis, older age was significantly associated with higher HZ severity-of-illness scores in both sexes: HZ severity increased by 11% and 6% in men and women, respectively, with each 1-year increase in age (Table 5). In men, worse health status and HSV seropositivity were associated with more severe HZ: HZ severity increased by 3% with each decreasing EuroQol unit; HSV seropositivity was associated with a 101% increase in HZ severity when compared to HSV seronegative men. In multivariate analyses, age was positively associated with HZ severity of illness in both men (10%) and women (6%; Table 5).
DISCUSSION
In our study, we found that HSV seronegativity was significantly higher among HZ cases than controls, with a 55% higher risk of HZ in HSV seronegative than HSV seropositive persons. This suggests that prior HSV infection provides protection against reactivation of VZV. While the incidence of HZ was lower in HSV seropositive persons, we observed that HZ severity was higher in persons with HSV infection.
The HSV seropositivity rate in this study population was 75%, with higher seropositivity in women than men, consistent with the overall age-adjusted HSV seropositivity reported for an older population in the time period in which the SPS was conducted [24]. Seroprevalence for HSV-1 was comparable to published data, while the seroprevalence for HSV-2 in the study population was lower than in older non-Hispanic white people in NHANES (11.9% vs 19.6%) [24]. The reasons for lower HSV-2 seropositivity in the SPS placebo arm than in the contemporaneous NHANES cohort are unknown but could include chronologic age and socioeconomic covariates.
Our data suggest that the protective effect of prior HSV infection on HZ incidence is stronger in men than women, while HSV seropositivity is associated with more severe HZ in men but not in women. Sex differences in disease outcomes have been observed for other viral infections [38], which can be attributed, in part, to differences in innate and adaptive immune responses. For example, the genes encoding Toll-like receptors 7 and 8 are X-linked, and some data indicate that X chromosome inactivation is imperfect, resulting in an effectively higher gene dosage for some proinflammatory factors [39]. While animal models for VZV generally do not mimic human infection well and sex differences for VZV pathogenesis have not been described, data from murine HSV models suggest an interaction between innate immunity genes and clinical outcomes [40]. The sex difference observed in the present report could be related to variation in the immune response to HSV, VZV, or both, potentially mediated by differences in sex steroid hormones and their interaction with the immune system [41]. Effects of sex differences in health care seeking behaviors on HZ incidence and severity were negligible in the SPS because of the active follow-up of all participants.
Previous studies have shown that prior infection with HSV-2 is protective against subsequent HSV-1 infection [42]. In addition, prior infection with HSV-1 ameliorates the severity of first-episode HSV-2 infection [43]. A study of facial nerve paralysis demonstrated that VZV reactivation as the underlying cause was frequent among HSV seronegative patients [44]. Taken together, these observations indicate that infection with one alphaherpesvirus can modulate infection with another alphaherpesvirus.
The current study was motivated by observations by our group and others [27–29] of human CD4 and CD8 T-cell cross-reactivity between HSV-1, HSV-2, and VZV. This was extensively documented at the whole-virus, full-length protein, peptide epitope, and T-cell receptor levels. Our study suggests that these ex vivo and in vitro observations are clinically meaningful, particularly in populations that have not received the newer, highly efficacious VZV glycoprotein E (gE) recombinant zoster vaccine (RZV; Shingrix) [45, 46]. The findings from this study may provide a rationale for the development of a prophylactic or therapeutic vaccine that protects from all 3 human alphaherpesviruses. The SPS and the Zoster Efficacy (ZOE) studies of RZV [32, 45, 46] have demonstrated that therapeutic vaccines can work effectively to prevent reactivation and subsequent replication of a latent human alphaherpesvirus. The adjuvanted RZV elicits strong gE-specific antibody and CD4 CMI responses [47] and is highly effective in reducing the incidence of both HZ and PHN [45, 46]. Of note, the VZV antigen in RZV, a truncated form of VZV gE, has only limited sequence homology to either HSV-1 or HSV-2. While HSV-VZV gE-specific cross-reactivity for CD4 T cells was noted in our prior study [30], the overall level of T-cell cross-reactivity for gE between HSV and VZV is predicted to be quite low due to sequence divergence. Based on the RZV or similar highly active vaccine platforms, a vaccine that utilizes cross-reactive T-cell epitopes and antigens may protect against both VZV and HSV infection or reactivation.
In contrast to HZ incidence, HZ severity was positively correlated with HSV infection, suggesting that the mechanisms underlying the reactivation of latent VZV to cause HZ may be different from those governing the severity and duration of HZ-associated pain. A randomized controlled trial demonstrating that corticosteroids, which have anti-inflammatory but not antiviral activity, ameliorate HZ pain, is consistent with this hypothesis [48]. The observation that in persons vaccinated with ZVL, protection against the severity of HZ-related pain and PHN is greater than protection against the incidence of HZ [49, 50] also supports this hypothesis.
To our knowledge, this is the first study that uses real-world data and specimens to determine whether prior HSV infection can provide cross-protection against HZ. Strengths of this study include the use of specimens and data from the SPS [32], a large prospective study of HZ with active follow-up, and granular clinical data. Another strength is the use of the University of Washington Western blot assay [37], with its high sensitivity and specificity for HSV-1 and HSV-2 serotyping.
Our study has limitations. While the number of participants was large enough to demonstrate an association between the occurrence of HZ and lack of HSV infection, the total number of HSV seronegative persons studied was small. Seventy-five percent of study participants were HSV seropositive, as expected in this age group. Study of a younger population might include more HSV seronegative persons, but the incidence of HZ would be lower. Only a few of our study participants were seropositive for HSV-2 alone or coinfected with HSV-1 and HSV-2. Thus, we were not able to perform type-specific analyses of the effect of prior HSV infection on the occurrence of HZ. Due to resource and specimen limitations, we were not able to perform T-cell studies on the participants in this study.
The SPS excluded persons with concomitant use of antiviral therapy, a history of recurrent herpes simplex with more than 3 episodes per year treated with episodic antiviral therapy (eg, 400 mg oral acyclovir 3 times daily for 5 days), and persons receiving daily antiviral therapy. However, we cannot rule out the possibility that some of the SPS participants used antivirals for HSV suppression, which could have affected both the incidence and the severity of HZ.
Due to the composition of the SPS, our population was limited to white persons. Consequently, the impact of race could not be evaluated. Our study did not include immunocompromised persons, who have a higher incidence of HZ and may be affected differently by HSV infection. Thus, our findings should be confirmed in other populations. The hypotheses underlying this study could be evaluated with a replication cohort from the placebo arm of the ZOE studies [45, 46], but samples are not currently available for this purpose. Populations that have received varicella vaccine or the adjuvanted HZ vaccine have very low rates of HZ, and thus the effect of HSV serostatus on VZV reactivation in vaccinated persons would be difficult to determine.
In summary, our study demonstrated that prior infection with HSV protects partly against reactivation of latent VZV to cause HZ. Lack of this cross-protection may contribute to the rising rates of HZ as rates of HSV infection decline.
Notes
Acknowledgments . The authors thank Dr Keith Jerome and his staff at the University of Washington Clinical Virology Laboratory for performing the HSV Western blot assay, Mr Kenneth Tapia for statistical support, Ms Donna Mussatto for expert administrative help, and the Veterans Medical Research Foundation for administrative support. The authors are grateful to the Shingles Prevention Study participants, without whom this study would not have been possible.
Financial support. This work was supported by the National Institutes of Health (grant number R21 AI153585 to D. M. K. and R. H.).
Contributor Information
Ruth Harbecke, Department of Veterans Affairs San Diego Healthcare System, San Diego, California, USA; Department of Medicine, University of California San Diego, San Diego, California, USA.
Michael N Oxman, Department of Veterans Affairs San Diego Healthcare System, San Diego, California, USA; Department of Medicine, University of California San Diego, San Diego, California, USA; Department of Pathology, University of California San Diego, San Diego, California, USA.
Stacy Selke, Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
Mark E Ashbaugh, Department of Veterans Affairs San Diego Healthcare System, San Diego, California, USA.
Kristine F Lan, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
David M Koelle, Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA; Benaroya Research Institute, Seattle, Washington, USA.
Anna Wald, Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Epidemiology, University of Washington School of Medicine, Seattle, Washington, USA.
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