Rev. Med. Virol. 2005; 15: 215–217.Published online in Wiley InterScience (www.interscience.wiley.com).

Reviews in Medical Virology DOI: 10.1002/rmv.474

A shot in the arm for immunotherapy

Immunisation has been spectacularly effective atpreventing acute viral diseases such as poliomye-litis, measles, mumps and rubella where the virusappears to be eradicated from the host after pri-mary infection. In contrast, many viruses persistincluding herpesviruses, HBV, HCV, HIV, polyo-maviruses and papillomaviruses. Many of theseviruses are responsible for major diseases such asAIDS and chronic hepatitis, while some cause can-cer. Collectively, they provide a major challengefor Public Health, as individuals live longer andas a higher proportion become immunocompro-mised, so facilitating chronic replication (HBV,HIV, HCV) and reactivation from latency (herpes-viruses).

Investigators have often wondered if giving vac-cine to those already infected could help to controldisease caused by persisting viruses. Such immu-notherapeutic use of vaccines has a chequered his-tory plagued by uncontrolled clinical observations(reviewed in [1]). The best example, so far, of a con-trolled study in humans, is the use of HSV-2 glyco-protein D vaccine using alum as an adjuvant [2].However, these initial promising findings were notfollowed up when a different preparation with a dif-ferent adjuvant failed to reproduce the beneficialfindings [3]. The science underlying immunothera-peutic responses and the laboratory correlates ofimmunity have, therefore, not been defined.

We now have a variety of experimentalapproaches to manipulate immune responses tovaccines including soluble recombinant proteins(which predominantly induce neutralising antibo-dies), DNA vaccines (cell mediated immunity),poxviruses/adenoviruses (cell mediated immu-nity) or live attenuated vaccines (which induceboth types of immune response). In addition, wehave several adjuvants which could be employedto stimulate preferentially those responses whichare beneficial; if only we knew what these desir-able responses are. Thus, one may formulate a ser-ies of questions: how do vaccines manage tocontrol acute infections? How do persisting

viruses evade these normal immune responses?Could immunotherapy stimulate responses nor-mally associated with control of virus replication?If so, could these responses be elicited by the samevaccines which are used to prevent initial infection?I will now attempt to address these questions inthe remaining 900 words.

Arguably, all licensed viral vaccines work byinducing neutralising antibodies which reducethe effective viral inoculum thus delaying andattenuating the disease process. These vaccines,therefore, prevent disease not infection.

Viruses which persist use a variety of mechan-isms to evade immune responses, both innateand adaptive. Examples include latency (herpes-viruses and HIV), inhibition of interferon path-ways (HCV, CMV), expression of chemokinereceptors to act as chemokine sinks (poxviruses,CMV), blockage of TAP the transporter of anti-genic peptides (HSV, CMV), decrease in HLA dis-play (CMV, HIV), providing decoys for naturalkiller cells (CMV) and mutation of critical epitopes(HIV, HCV). These strategies have been cate-gorised and contrasted as ‘hiding’ (typically her-pesviruses) and ‘running’ (typically HIV, HCV)from established host responses [4]. The combinedeffects of the various strategies are so effective thatthey might imply that it is futile to attempt to usethe immune system to control persisting viruses.Nevertheless, persisting viral infections can becontrolled if the initial phase of replication is tar-geted. Examples include HBV (our first vaccineagainst human cancer), HPV (our second vaccineagainst human cancer) and VZV [5–9]. This per-spective implies that disease due to persistencerequires the rapid establishment of a high initialviral load. It also suggests that pre-existing neutra-lising antibody may be sufficient to prevent theinitial infection. However, once a persisting virushas been allowed to establish infection, then onlycell mediated immunity can keep it suppressedinto sites of persistence, with eradication the out-come for only a fortunate few. This implies that a

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different vaccine may be required from one that isused for prevention; unless a live attenuated vac-cine, which induces both cell mediated andhumoral immunity, is used.

Given this background, the authors of a recentpaper must be congratulated for performing adouble-blind randomised placebo-controlled trialof VZV live attenuated vaccine using a preparationwhich contained approximately 14 times the num-ber of plaque forming units of the same Oka strainwhich is found in the current VZV vaccine [10].VZV causes both chickenpox and zoster, with theburden of ill health and healthcare costs greater forthe latter [11]. The motivation of the investigatorswas to reduce the considerable morbidity asso-ciated with zoster, measured as post herpetic neur-algia (or zoster associated pain), quality of life andinterference with activities of daily living amongthe elderly [12]. In this study 38,546 people aged>60 years (median age 69 years) who had a historyof chickenpox, or had resided in the USA for atleast 30 years, were randomly allocated to receivevaccine or placebo. They were followed up for anaverage of 3.1 years for recurrences of zoster andthe results show significant reductions in boththe incidence and severity of zoster. Over 95% ofrecruited patients completed the planned followup and zoster was confirmed by PCR in 93% ofcases (which also showed that no cases of zosterwere caused by the vaccine strain). Overall, 315cases of zoster occurred in the vaccinated groupcompared to 642 in the placebo group (rates of5.4 vs 11.1 per 1000 person-years of follow uprespectively), representing a 51% reduction in inci-dence. Post herpetic neuralgia developed in 27recipients of vaccine compared to 80 recipients ofplacebo thus representing a 67% reduction. Theprimary end point of burden of illness (area underthe curve of pain severity vs time) was reduced by61% among vaccine recipients.

We can conclude that a second exposure to VZVin the form of the same vaccine strain which canprevent chickenpox is able to delay significantlythe future development of zoster and also reduceits severity. Therefore, it seems likely that expo-sure to ‘natural’ chickenpox may also provide asimilar immune boost; a hypothesis first proposedby Hope-Simpson in 1965 [13]. This hypothesis issupported by the finding of a selective decreasein cell-mediated, but not humoral, immunity inthe elderly [14,15] coupled with boosting of

humoral and cell-mediated immunity specific forVZV after re-exposure to chickenpox [16]. Furtherevidence is also provided by studies where house-hold, social or occupational contact with childrenwas shown to be protective against zoster in adults[17,18]. Those of us chronically paying school anduniversity fees will no doubt be delighted to hearof some tangible benefit from this investment;however, the results of the recent trial show thatthe benefit (as far as VZV is concerned) can beachieved via a simpler (and much cheaper!) doseof vaccine.

These results indicate that the VZV vaccinescould now be applied to prevent both chickenpoxand zoster. Indeed, countries like the UK haveheld back from universal childhood immunisationbecause of concerns that reducing the number ofcases of chickenpox may decrease the secondaryantigenic stimulation which helps to keep VZVsuppressed into latency [11]. The existing vaccinecould now be given to children, to prevent chick-enpox, and the new vaccine given to the elderly, toprevent zoster (including the additional zostercases attributable to reduced antigenic boostsbecause of the control of chickenpox). Formalcost benefit analyses will be needed, but a broadstrategic response to both diseases caused byVZV may be easier to justify than the incrementalcosts of introducing a zoster prevention schemeonce childhood immunisation has already begun(as in the USA). It will be critical to determinehow frequently booster doses of vaccine will beneeded to keep VZV suppressed into latency,with mathematical models suggesting that naturalimmunity protects against zoster for an average of20 years [17]. The results of examining specificimmune responses, (such as CD4þ T-cell stimula-tion in response to VZV [19] or IFN-gammaELISpot production [20], as potential correlates ofprotection against zoster may help, and should beintegrated into the decision-making process.

P D Griffiths

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simplex virus type 2 for immunotherapy of genitalherpes. Lancet 1994; 343(8911): 1460–1463.

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10. Oxman MN, et al. A Vaccine to Prevent Herpes Zos-ter and Postherpetic Neuralgia in Older Adults. NEngl J Med 2005; 352(22): 2271–2284.

11. Brisson M, Edmunds WJ. Varicella vaccination inEngland and Wales: cost-utility analysis. Arch DisChild 2003; 88(10): 862–869.

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17. Brisson M, Gay NJ, Edmunds WJ, Andrews NJ.Exposure to varicella boosts immunity to herpes-zos-ter: implications for mass vaccination against chick-enpox. Vaccine 2002; 20(19–20): 2500–2507.

18. Thomas SL, Wheeler JG, Hall AJ. Contacts with var-icella or with children and protection against herpeszoster in adults: a case-control study. Lancet 2002;360(9334): 678–682.

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20. Levin MJ, Smith JG, Kaufhold RM, Barber D,Hayward AR, Chan CY, et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated immunitywith increasing age and boosting with a high-hoseVZV vaccine. J Infect Dis 2003; 188(9): 1336–1344.

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