Literature review on the immunogenicity of herpes zoster vaccines

Executive Summary

Herpes zoster is an acute viral infection caused by reactivation of varicella-zoster virus (VZV). LZV, a live, attenuated vaccine for zoster has been available in Canada for many years. A new subunit recombinant zoster vaccine (RZV) named Shingrix was approved in Canada in October 2017. This zoster vaccine immunogenicity review was done to have a comprehensive understanding of the immunogenicity of both live and subunit vaccines. This immunogenicity review was done in conjunction with a larger review of the clinical efficacy and safety of zoster vaccines that supported recommendations in the NACI Statement titled “Updated Recommendations on the Use of Herpes Zoster Vaccines” published August 30, 2018 .

A search strategy was developed with a federal Reference Librarian (Health Library) and was verified by the NACI Zoster Working Group. Four databases (MEDLINE, EMBASE, Cochrane Central, and PsychInfo) were queried on June 5, 2017 (updated October 12, 2017). Through this literature review, 52 relevant studies were included in the evidence synthesis. In addition to this search, a review of herpes zoster vaccine related posters from IDWeek 2017 as done to obtain the most current information. These studies assessed the immunogenicity of live vaccine in general and special populations, the immunogenicity of RZV in general and special populations, and concomitant administration with other vaccines. The type of evidence retrieved on the topic was diverse and included randomized controlled trials and cohort studies with quality of evidence ranging from good to poor.

The humoral and cellular correlates of protection from zoster among patients who have had VZV are not clear and none have been clearly established as markers of protection ^{Footnote 1},^{Footnote 2}. It does appear that CD4+ and CD8+ cells play a central role in preventing VZV reactivation ^{Footnote 3}. Furthermore, commercially available laboratory tests for assessing immunity from natural VZV infection are not accurate for diagnosing immunity from prior vaccination ^{Footnote 4}. Therefore, studies evaluating the immunogenicity of zoster vaccination should be interpreted with caution. 

LZV was found to be immunogenic in all studies in the general population. Among live vaccine studies, humoral immunity was generally measured in levels of Anti-VZV antibodies while cell-mediated immunity was measured through VZV-specific IFN-gamma spot-forming cells with ELISPOT or through a responder cell frequency assay of CD4+ memory cells. The duration of follow-up was up to 3 years ^{Footnote 5}, suggesting protection extends at least that long. It appears that cell-mediated immunity and the rate of rise in anti-VZV titres were most correlated with clinical protection, rather than absolute levels of anti-VZV antibodies ^{Footnote 6},^{Footnote 7}. The immune response among those aged 50-59 appears more robust than those over the age of 60 ^{Footnote 8},^{Footnote 9},^{Footnote 10}. LZV was also generally immunogenic among immunocompromised populations, whether through a disease or through immunosuppressive therapies ^{Footnote 11},^{Footnote 12}. Among patients with hematologic malignancies ^{Footnote 13},^{Footnote 14},^{Footnote 15}, solid tumor malignancies^{Footnote 13}, rheumatoid arthritis on immunosuppressive treatments ^{Footnote 16}, inflammatory bowel disease patients on immunomodulators ^{Footnote 17},^{Footnote 18}, and HIV patients with CD4 count <200 ^{Footnote 13}, live attenuated vaccine was found to be immunogenic. It was only among certain groups of patients with hematopoietic stem cell transplants where immune responses were not elicited. Concurrent administration of LZV with other vaccines like pneumococcal or influenza vaccine does not appear to affect immunogenicity compared to non-concurrent vaccination ^{Footnote 19},^{Footnote 20}.

Similarly, the RZV vaccine was immunogenic in all studies in the general population. Among subunit vaccine studies, humoral immunity was generally measured by levels of Anti-gE antibodies while cell-mediated immunity was measured through levels of CD4+ cells with at least two activation markers (including expression of IFN-gamma, IL-2, TNF-a, or CD40 ligand). The longest follow-up was for 9 years and demonstrated immune markers elevated from baseline ^{Footnote 21}. Unlike the live vaccine, RZV appears to be similarly immunogenic across all adults over 50 years of age ^{Footnote 22},^{Footnote 23}. There appear to be no changes in immunogenicity when it is given with or without a live vaccine ^{Footnote 24} such as the live varicella zoster vaccine Varilrix.  One abstract also suggested that RZV is immunogenic for patients who have been previously vaccinated with the live vaccine at least 5 years prior to RZV administration (mean duration 6.7 years), with no differences in immunogenicity among those with and without prior live vaccine ^{Footnote 25}. RZV also appears to be immunogenic among immunocompromised populations. One study demonstrated robust CMI and humoral immunity for HIV patients, even with CD4 counts <200 if on ART ^{Footnote 26}. Another study suggested that for patients with autologous hematopoietic stem cell transplant, RZV was able to elicit a significant humoral and CMI response ^{Footnote 27}. Three abstracts suggested that RZV was at least partially immunogenic among patients with hematologic malignancy ^{Footnote 28}, solid tumor malignancy ^{Footnote 29}, and among renal transplant patients with chronic immunosuppressive therapy ^{Footnote 30}. One study suggested that concurrent administration of RZV with influenza vaccine was not associated with diminished immunogenicity ^{Footnote 31}.

One head-to-head study currently only available in abstract format suggested that RZV may be better at eliciting a memory T-cell response than LZV ^{Footnote 32}.

Ultimately, there is a large body of data suggesting that both LZV and RZV are immunogenic in both the general and special populations. It also appears plausible, through one head-to-head study, that RZV is potentially more immunogenic than LZV based on a superior memory T-cell response.

The literature review is available through the Government of Canada Publications website. To obtain the report in an alternative format, please contact us by email: phac.naci-ccni.aspc@canada.ca.