Varicella-Zoster Virus: A rare success story
Part 3 of “The human herpesviruses: much more than you wanted to know”.
Note: Part 1 of this series (an introduction to herpesviruses) is here and part 2 (HSV) is here.
0. If you don’t want to read this whole post, remember this actionable advice:
Get vaccinated for VZV.
If you have chickenpox, don’t take aspirin.
1. Introduction
Human herpesvirus 3 is better known as varicella-zoster virus (VZV). This name comes from the diseases it causes: chickenpox (varicella) during primary infection, and shingles (herpes zoster) during reactivation. As an alphaherpesvirus, it shares many similarities with HSV1 and HSV2, including initial infection of the epithelium and establishment of latency within neurons.
Notably, VZV is the only human herpesvirus to have vaccines approved against it. These vaccines are a real success story, and understanding how they work is quite important when considering the potential for vaccines against other herpesviruses. But first, let’s discuss VZV biology.
2. Virology of VZV
Like the other alphaherpesviruses, VZV has a linear double-stranded DNA genome. At 125 kbp, it is slightly smaller than HSV, and is the smallest human herpesvirus. The viral replication cycle is very similar to that of HSV which I wrote about previously, so I’ll just point out some key differences (1):
VZV has some different surface glycoproteins (lacking gD, and having variations in some of the others). This is probably what enables respiratory transmission. However, gB is highly similar between HSV and VZV, probably because variation reduces fitness.
VZV doesn’t express LAT, and has a somewhat different mechanism controlling latency vs. activation. It has a VP16 homolog, but a different protein called IE62 is more important.
3. Pathophysiology of VZV
Primary infection with VZV causes chickenpox. Initially, the virus replicates at the site of entry (usually the respiratory tract) before spreading throughout the entire body via infected white blood cells. The time from initial infection to appearance of symptoms is typically 14 to 16 days, although this can vary. Importantly, individuals are infectious a few days before appearance of symptoms.
In contrast to other herpesviruses, primary VZV infection nearly always causes symptoms. The classic symptom is a rash of itchy blisters (usually 250 to 500 in total) across the surface of the body and the inside of the mouth and nose. This is usually accompanied by a low-grade fever. For immunocompetent children, chickenpox usually is not a serious disease. However, in rare cases neurological complications can occur, such as cerebellar ataxia (1 in 4,000) or encephalitis (1 in 50,000). One important note is that if aspirin is taken during chickenpox (or certain other viral infections), it can cause a complication known as Reye syndrome. This appears to be specific to aspirin, and other NSAIDs (such as ibuprofen) are safe.
Primary VZV infection during adulthood is often more serious. Whereas hospitalization rates in unvaccinated children are around 1–2 per 1,000 cases, they are about 14 per 1,000 in adults. My girlfriend’s cousin’s wife (living in Poland where vaccination is less common) recently contracted chickenpox from her son, and was hospitalized. Complications can include pneumonia, as well as secondary bacterial infections. If VZV causes a primary infection in a pregnant woman, it can occasionally (<2% risk) cross the placenta and spread to the fetus, causing severe complications.
VZV reactivation causes shingles (herpes zoster), which presents as a chickenpox-like rash on a region of the body, typically accompanied by burning pain. The affected region usually corresponds to the area connected with a single spinal nerve. Individuals with latent VZV (i.e., the vast majority of the adult population) have a lifetime risk of shingles of approximately 1 in 3. The rate is more frequent in older adults with weaker immune systems. Complications of shingles can include persistent nerve pain (occurring in ~9% of cases), weakness, blindness if the eye is involved, or hearing loss if the ear is involved. Nucleoside antiviral medications such as acyclovir can help treat the symptoms.
4. Epidemiology of VZV
Prior to the development of VZV vaccines, nearly all people were infected by adulthood. Interestingly, chickenpox outbreaks follow a seasonal pattern, with peak transmission in the late winter and early spring. In tropical countries, VZV transmission occurs less readily, such that the average age of infection is older than in temperate countries.
VZV is highly contagious, with 61 – 100% of susceptible household contacts of a chickenpox case becoming infected. Transmission can occur by respiratory particles or contact with blisters. It is likely that the respiratory route accounts for the majority of spread. As such, shingles (which typically has negligible respiratory shedding) is approximately 1/5 as contagious as chickenpox.
Since the introduction of VZV vaccines in the late 1990s, rates of infection have declined ~97% in the United States. This represents a huge success. Other countries with lower vaccination rates have higher infection rates.
5. VZV Vaccines
Currently there are two FDA-approved vaccines for VZV (I’m counting different formulations of the same vaccine as one vaccine.)
The first to be developed was a live-attenuated strain, produced by serial passage of a wild-type virus in cell culture during the 1970s. The process of serial passage resulted in the virus undergoing genetic drift (mutations) that reduced its fitness to infect humans rather than cell lines. The “vaccine virus” is actually a population of mutated viruses, with 235 – 336 different mutations identified depending on the batch (2).
This is a very old-school method of making attenuated viruses, but in this case it was successful. The live-attenuated VZV vaccine is highly effective in preventing chickenpox after two doses, and breakthrough cases that do occur are usually mild. Interestingly, the vaccine is also effective for post-exposure prophylaxis, if given within 3 days of exposure. A different formulation of the vaccine (Zostavax) is approved to prevent shingles by boosting immunity in older adults.
Since the live-attenuated vaccine is a live virus, it still replicates within the host and establishes latency. This is actually a good thing since it ensures persistent protection. However, it can sometimes cause disease in immunocompromised people, and even can be transmitted between individuals (although it is much less infectious than wild-type). In rare cases, the vaccine virus can even mutate back to a more virulent form, although this is still not as bad as the wild-type virus (2). This is because the mutations that occurred during serial passage did not actually delete the viral genes, just inactivate them, leaving open the possibility for mutations to restore their function.
In order to allow the immunization of elderly adults with weakened immune systems who may not tolerate the live-attenuated vaccine, a recombinant protein vaccine (Shingrix) was developed by GlaxoSmithKline. This vaccine is a mixture of a truncated form of VZV gE and several adjuvants, including a saponin and lipopolysaccharide, which activate the immune system. It has been shown to be highly effective (94 – 99%) in preventing shingles over a 3-year follow-up period (3). It is unclear whether it would also be effective in preventing primary VZV infection.
The successes of VZV vaccines have shown that it is possible to vaccinate against an alphaherpesvirus. However, many of the same strategies for VZV vaccines have already been tested against other herpesviruses, with disappointing results. Herpesvirus vaccines aren’t impossible (at least for alphaherpesviruses), but some innovation will be needed. I’ll discuss this more in a later post in this series.
6. My status
I received one dose of the live-attenuated VZV vaccine as an infant, but was infected with wild-type virus before my second dose. According to my parents, my case was very mild. Anyway, this means that I have two separate strains of VZV latent within my body.
7. References and further reading
Much of the information in this post came from the CDC Pink Book, which you can read here: https://www.cdc.gov/vaccines/pubs/pinkbook/varicella.html
Other sources:
A. M. Arvin, Varicella-zoster virus. Clin Microbiol Rev. 9, 361–381 (1996).
D. P. Depledge, S. Kundu, N. J. Jensen, E. R. Gray, M. Jones, S. Steinberg, A. Gershon, P. R. Kinchington, D. S. Schmid, F. Balloux, R. A. Nichols, J. Breuer, Deep Sequencing of Viral Genomes Provides Insight into the Evolution and Pathogenesis of Varicella Zoster Virus and Its Vaccine in Humans. Molecular Biology and Evolution. 31, 397–409 (2014).
H. Lal, A. L. Cunningham, O. Godeaux, R. Chlibek, J. Diez-Domingo, S.-J. Hwang, M. J. Levin, J. E. McElhaney, A. Poder, J. Puig-Barberà, T. Vesikari, D. Watanabe, L. Weckx, T. Zahaf, T. C. Heineman, Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults. N Engl J Med. 372, 2087–2096 (2015).