Varicella Vaccine: a Molecular Variant That May Contribute to Attenuation.

Varicella was troublesome when varicella vaccine (vOka) was licensed in the United States. Varicella's yearly death toll was ~100, indirect costs were massive, and varicella threatened immunocompromised children. Since licensure, varicella has almost disappeared; nevertheless, vOka attenuation has lacked a molecular explanation. Sadaoka et al. (T. Sadaoka, D. P. Depledge, L. Rajbhandari, J. Breuer, et al., mBio 13:e0186422, 2022, https://doi.org/10.1128/mbio.01864-22), however, have now identified 6 core single nucleotide polymorphisms (SNPs), which singly or in combination may contribute to VOka attenuation; moreover, they found a predominant variant allele of vOka encoding the viral glycoprotein gB that results in glutamine instead of arginine at amino acid 699. This change impairs fusion activity and the ability of varicella-zoster virus (VZV) to infect human neurons from axon terminals. Molecular virological studies of vOka are reassuring in suggesting that reversion to virulence is unlikely and should also help assuage current fears about VZV vaccination and alleviate unanticipated future problems. The impressive work of Sadaoka et al. thus represents an auspicious advance in knowledge.

Clinical Manifestations of Varicella: Disease Is Largely Forgotten, but It's Not Gone.

After 25 years of varicella vaccination in the United States, classic varicella and its complications have become an uncommon occurrence. The clinical manifestation of varicella among vaccinated persons is usually modified, with fewer skin lesions, mostly maculopapular, and milder presentation. However, the potential for severe manifestations from varicella still exists among both vaccinated and unvaccinated persons, and thus healthcare providers should keep varicella in the differential diagnosis of a maculopapular or vesicular rash. The prompt recognition and diagnosis of varicella is important because when confirmed, clinical and public health measures need to be taken swiftly.

KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine.

Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered.

Live Attenuated Varicella Vaccine: Prevention of Varicella and of Zoster.

Michiaki Takahashi developed the live attenuated varicella vaccine in 1974 . This was the first, and is still the only, herpesvirus vaccine. Early studies showed promise, but the vaccine was rigorously tested on immunosuppressed patients because of their high risk of fatal varicella; vaccination proved to be lifesaving. Subsequently, the vaccine was found to be safe and effective in healthy children. Eventually, varicella vaccine became a component of measles mumps rubella vaccine, 2 doses of which are administered in the USA to ~90% of children. The incidence of varicella has dropped dramatically in the USA since vaccine-licensure in 1995. Varicella vaccine is also associated with a decreased incidence of zoster and is protective for susceptible adults. Today, immunocompromised individuals are protected against varicella due to vaccine-induced herd immunity. Latent infection with varicella zoster virus occurs after vaccination; however, the vaccine strain is impaired for its ability to reactivate.

Communicability of varicella before rash onset: a literature review.

Varicella poses an occupational risk and a nosocomial risk for susceptible healthcare personnel and patients, respectively. Patients with varicella are thought to be infectious from 1 to 2 days before rash onset until all lesions are crusted, typically 4-7 days after onset of rash. We searched Medline, Embase, Cochrane Library and CINAHL databases to assess evidence of varicella-zoster virus (VZV) transmission before varicella rash onset. Few articles (7) contributed epidemiologic evidence; no formal studies were found. Published articles reported infectiousness at variable intervals before rash onset, between <1 day to 4 days prior to rash, with 1-2 patients for each interval. Laboratory assessment of transmission before rash was also limited (10 articles). No culture-positive results were reported. VZV DNA was identified by PCR before rash onset in only one study however, PCR does not indicate infectivity of the virus. Based on available medical literature, VZV transmission before rash onset seems unlikely, although the possibility of pre-rash, respiratory transmission cannot be entirely ruled out.

Safety and Varicella Outcomes in In Utero-Exposed Newborns and Preterm Infants Treated With Varicella Zoster Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access Program.

BACKGROUND: Infants exposed to varicella zoster virus (VZV) in utero ≤5 days before or ≤48 hours after delivery and preterm infants are at high risk for varicella complications. An expanded-access program assessed varicella outcomes after administration of varicella zoster immune globulin (human) (VARIZIG) in a real-world setting. METHODS: In this open-label, expanded-access program, high-risk infants received ≤125 IU/10 kg of VARIZIG (NCT00338442). VZV outcomes and safety were assessed. RESULTS: There were 43 newborns exposed to VZV in utero and 80 preterm infants exposed to VZV; >80% received VARIZIG within 96 hours of reported exposure. When varicella outcomes were available, varicella occurred in 7 of 38 (18%) in utero-exposed newborns and zero of 65 preterm infants. Varicella-related complications were reported in 3 in utero-exposed newborns (3 with >100 lesions, 1 each with encephalitis and pneumonia). Adverse events were reported for 16% of in utero-exposed newborns and 25% of preterm infants, but few were considered related to VARIZIG. There were no deaths attributable to varicella or VARIZIG. CONCLUSIONS: Varicella incidence and morbidity were low in in utero-exposed infants and zero in preterm infants who received prophylactic VARIZIG. There were few VARIZIG-related safety concerns.

Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review.

CONTEXT: Live vaccines usually provide robust immunity but can transmit the vaccine virus. OBJECTIVE: To assess the characteristics of secondary transmission of the vaccine-strain varicella-zoster virus (Oka strain; vOka) on the basis of the published experience with use of live varicella and zoster vaccines. DATA SOURCES: Systematic review of Medline, Embase, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and Scopus databases for articles published through 2018. STUDY SELECTION: Articles that reported original data on vOka transmission from persons who received vaccines containing the live attenuated varicella-zoster virus. DATA EXTRACTION: We abstracted data to describe vOka transmission by index patient's immune status, type (varicella or herpes zoster) and severity of illness, and whether transmission was laboratory confirmed. RESULTS: Twenty articles were included. We identified 13 patients with vOka varicella after transmission from 11 immunocompetent varicella vaccine recipients. In all instances, the vaccine recipient had a rash: 6 varicella-like and 5 herpes zoster. Transmission occurred mostly to household contacts. One additional case was not considered direct transmission from a vaccine recipient, but the mechanism was uncertain. Transmission from vaccinated immunocompromised children also occurred only if the vaccine recipient developed a rash postvaccination. Secondary cases of varicella caused by vOka were mild. LIMITATIONS: It is likely that other vOka transmission cases remain unpublished. CONCLUSIONS: Healthy, vaccinated persons have minimal risk for transmitting vOka to contacts and only if a rash is present. Our findings support the existing recommendations for routine varicella vaccination and the guidance that persons with vaccine-related rash avoid contact with susceptible persons at high risk for severe varicella complications.

Varicella zoster immune globulin (VARIZIG) administration up to 10 days after varicella exposure in pregnant women, immunocompromised participants, and infants: Varicella outcomes and safety results from a large, open-label, expanded-access program.

INTRODUCTION: Despite vaccination, there were more than 100,000 annual cases of varicella in the United States in 2013-2014. Individuals at highest risk of developing severe or complicated varicella include immunocompromised people, preterm infants, and pregnant women. Varicella zoster immune globulin (human) (VARIZIG) is recommended by the CDC for postexposure prophylaxis to prevent or attenuate varicella-zoster virus infection in high-risk individuals. Contemporary information on administration of VARIZIG is limited. METHODS: This open-label, expanded-access program provided VARIZIG to physician-identified, high-risk participants exposed to varicella. Participants included immunocompromised children/adults, infants (preterm, newborns whose mothers had varicella onset within 5 days before or 2 days after delivery, and those aged <1 year), and pregnant women. VARIZIG (125 IU/10 kg [up to 625 IU]) was administered intramuscularly, ideally within 96 hours, but up to 10 days, postexposure. Incidence of varicella rash and severity (>100 pox, pneumonia, or encephalitis) were assessed up to 42 days after administration. RESULTS: The varicella outcome population (n = 507) included 263 immunocompromised participants (32 adults, 231 children), 137 pregnant women, 105 infants, and 2 healthy adults with no history of varicella. Varicella incidence was 4.5% in immunocompromised participants, 7.3% in pregnant women, and 11.5% in infants. The incidence of varicella was similar when comparing VARIZIG administration ≤ 96 hours vs > 96 hours (up to 10 days) postexposure in the entire population (6.2% vs. 9.4%, respectively), and also in each subgroup. Of 34 participants with varicella, 5 developed > 100 pox and 1 developed pneumonia and encephalitis. There were no product-related deaths and only 1 serious adverse event (serum sickness) considered probably related to VARIZIG. CONCLUSION: Postexposure administration of VARIZIG was associated with low rates of varicella in high-risk participants, regardless of when administered within 10 days postexposure. VARIZIG was well-tolerated and safe in high-risk participants.

The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting.

BACKGROUND: A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. METHODS: An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo-0%Endo, 75%Exo-25%Endo, 50%Exo-50%Endo, 25%Exo-75%Endo, 0%Exo-100%Endo. RESULTS: HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. CONCLUSIONS: Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

High Constitutive Interleukin 10 Level Interferes With the Immune Response to Varicella-Zoster Virus in Elderly Recipients of Live Attenuated Zoster Vaccine.

INTRODUCTION: Live attenuated zoster vaccine (Zostavax) was used to test the hypothesis that constitutive level of interleukin 10 (IL-10), which may be high in elderly subjects, impairs vaccine efficacy. If constitutive IL-10 impairs vaccine efficacy, the effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination. METHODS: Zostavax was given to 26 patients (age, 60-80 years). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) assays and glycoprotein enzyme-linked immunosorbent assays (gpELISAs) were used to assess humoral immunity; anti-varicella virus T-cell responses were studied in a subset of subjects. In a prospective animal model, T-cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10. RESULTS: FAMA assays revealed significant boosting (by 4-fold) of humoral immunity, which occurred only in subjects (10 of 26) with a low constitutive IL-10 level (ie, <20 pg/mL); moreover, the Zostavax-induced FAMA and gpELISA responses were inversely related to the constitutive IL-10 level. Significant VZV-specific T-cell responses followed vaccination only in subjects with a low constitutive IL-10 level. Vaccine-induced LCMV-specific T-cell responses in mice lacking IL-10 were greater than in wild-type animals. CONCLUSIONS: A high constitutive IL-10 level adversely affects vaccine efficacy.

Clinical Features of Varicella-Zoster Virus Infection.

Varicella-zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (chickenpox) as a primary infection, following which it becomes latent in peripheral ganglia. Decades later, the virus may reactivate either spontaneously or after a number of triggering factors to cause herpes zoster (shingles). Varicella and its complications are more severe in the immunosuppressed. The most frequent and important complication of VZV reactivation is postherpetic neuralgia, the cause of which is unknown and for which treatment is usually ineffective. Reactivation of VZV may also cause a wide variety of neurological syndromes, the most significant of which is a vasculitis, which is treated with corticosteroids and the antiviral drug acyclovir. Other VZV reactivation complications include an encephalitis, segmental motor weakness and myelopathy, cranial neuropathies, Guillain⁻Barré syndrome, enteric features, and zoster sine herpete, in which the viral reactivation occurs in the absence of the characteristic dermatomally distributed vesicular rash of herpes zoster. There has also been a recent association of VZV with giant cell arteritis and this interesting finding needs further corroboration. Vaccination is now available for the prevention of both varicella in children and herpes zoster in older individuals.

Tale of two vaccines: differences in response to herpes zoster vaccines.

About one-third of the US population will develop herpes zoster (HZ, commonly known as shingles) over a lifetime, while two-thirds will not. It is not clear exactly why certain people are susceptible to HZ; however, we may be coming closer to an answer. In this issue of the JCI, a study by Levin et al. provides important details concerning pathogenesis of and protection from HZ. The authors characterized differences in the immunologic responses induced by two HZ vaccines, the live attenuated zoster vaccine (ZV) and the more recently developed adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su), in vaccine-naive subjects and those previously vaccinated with HZ. The observed differences in responses paralleled the observed clinical protection of the two zoster vaccines, with HZ/su being superior to HZ. Together, these results seem to explain immunologically why the new subunit vaccine outperforms the live vaccine. These differences may also provide clues as to why HZ develops in the first place.

Varicella Virus Vaccination in the United States.

Varicella zoster virus (VZV) is the cause of chickenpox (varicella) and shingles (zoster), and was once responsible for over 4 million infections in the United States annually. The development of a live attenuated VZV vaccine was initially viewed with extreme skepticism. Nonetheless, a VZV vaccine was developed in the 1970s by Takahashi and his colleagues in Japan and was eventually licensed in the US. It is now known to be one of the safest and most effective vaccines available and is administered worldwide. Here are described important factors that contributed to the successful research and licensure of the highly successful VZV vaccine.