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British Medical Bulletin 62:125-138 (2002)
© 2002 The British Council
Vaccines against persistent DNA virus infections
Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Abstract
Herpes virusesPersistent viruses present some particular problems for vaccine design. As for acute non-persistent viruses, the prime goal of a vaccine should be to prevent primary infection. Vaccines might also be used to modify the course of established persistent virus infections – so-called postinfective immunisation. This chapter deals with selected persistent DNA viruses, in particular the human herpes viruses.
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Herpes viruses |
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The family of herpes viruses is widely distributed in the animal kingdom and comparative sequence analysis suggests they have been co-evolving with their individual hosts for millions of years. Eight human herpes viruses have been identified to date (Table 1), and are assigned to three subfamilies, the alpha- beta- and gamma-herpesvirinae, on the basis of shared genomic and biological properties. All the herpes viruses are characterised by a linear, double-stranded DNA genome, contained inside an icosahedral capsid, which is surrounded by a protein tegument and the outer lipid envelope containing virus glycoprotein spikes. Although differing in many of their biological properties, all herpes viruses share the capacity to produce persistent latent infection in their natural host, during which the viral genome persists in cells with only a limited subset of viral genes being expressed: this property is key to their ability to produce persistent, life-time infection of the host. In response to subsequent activation/differentiation of latently-infected cells, viral re-activation from latency produces infectious virus particles which are shed from body surfaces. Their associated diseases may result from primary infection or re-activation from latency, and tend to be more severe in immunosuppressed patients. Healthy carriers of herpes viruses usually make strong sustained immune antibody and T cell immune responses against these viruses, and analysis of these immune responses has informed the design of candidate subunit vaccines. Postinfective vaccination attempts to enhance pre-existing immune responses, to reduce the frequency and/or severity of clinical re-activation episodes.
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Vaccination against herpes simplex virus (HSV) |
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Disease caused by HSV The genomes of HSV-1 and HSV-2 are largely co-linear. Antigenic differences in the surface glycoprotein G are used to distinguish between HSV-1 and HSV-2. The virus infects a relatively wide range of cells in vitro, and can also infect experimental animals allowing studies of its pathogenesis.
The seroprevalence is 70–90% in lower, but only about 30% in higher, socio-economic groups by the age of 10 years, whereas by mid-life 80–90% of all individuals have antibody to HSV-1. HSV-2 infection is usually acquired through sexual contact, with a progressive increase in seroprevalence beginning in adolescence. The number of sexual contacts is a major risk factor for acquisition of HSV-2: seroprevalence rates in adults vary from 10–80% depending on the population and risk factors.
Transmission occurs by direct contact of a susceptible individual with infected secretions from an HSV carrier, usually from oral, genital or skin lesions to mucous membranes. A recent study (an unsuccessful vaccine trial) showed only 60% of primary infection with HSV-1, and 40% with HSV-2, was symptomatic in sexually active subjects1. The clinical manifestations of the two viruses overlap, but HSV-1 is the predominant cause of oro-facial infections and HSV-2 of genital HSV infection. Around 25% of HSV-1 seropositive individuals have recurrent re-activation episodes with oro-labial lesions. The recurrence rate of genital herpes is around 3–4 attacks per year when due to HSV-2, but less for HSV-1. Despite extensive study no difference in immune responses to HSV between those with frequent reactivation episodes, and those without, have been reproducibly established. Encephalitis is the most serious type of disease produced by HSV in the normal immunocompetent host, with an estimated annual incidence of 2–3 cases per million of population. HSV can be transmitted to the neonate by infection (usually HSV-2) from maternal genital secretions at the time of delivery.
Vaccines against HSV There is, as yet, no licenced vaccine available for HSV, although several candidates are approaching phase III trials. There is particular interest in postinfective immunisation to determine whether this can reduce the frequency of recurrent genital HSV attacks.
Vaccines designed to prevent HSV have been aimed almost exclusively at preventing genital HSV disease, given its perceived greater importance in terms of patient suffering. Vaccines against HSV might either be directed at preventing primary infection by induction of ‘sterilising immunity’, or aimed at preventing or limiting disease without actually preventing acquisition of latent infection: it is relevant here that there is some evidence genital HSV-2 infection is symptomatically less severe in individuals who have prior immunity to HSV-1. Experimental studies in mice and guinea pig models of genital tract HSV infection indicate that some degree of protection can be produced by candidate vaccines. In addition, in the guinea pig model, there is some evidence that postinfective immunisation can limit the severity of recurrent genital tract HSV disease2,3.
It is thought that any effective vaccine would probably need to induce both virus-specific T-cell (CD4 and CD8) responses and antibody-mediated immunity, including mucosal immunity. A number of approaches have been used to develop candidate HSV vaccines.
Inactivated whole virus vaccines
A number of earlier candidates were developed using this approach but none have proved as immunogenic as wild-type virus or replicating vaccines and, of those that reached clinical trials, none were effective2.
Subunit vaccines
A number of subunit vaccines have been developed based on envelope glycoproteins which are thought to be major targets for neutralising antibody, particularly glycoproteins gB and gD. A vaccine containing recombinant gB and gD from HSV-2 with adjuvant did not show effective protection in preventing acquisition, or recurrence, of genital HSV-2 infection4,5. A further subunit vaccine based on gD from HSV-2 with alum and monophosphoryl lipid A as adjuvant has been shown to induce immune responses and is currently in phase III studies (cited in Stanberry et al2). DNA vaccines, mainly using plasmids expressing gB and gD genes are also being developed by several groups, and give protection in experimental models of HSV6, but to the authors' knowledge none has progressed beyond phase II studies. Clinical trials of the subunit vaccines have been both of the primary prevention and therapeutic type: for primary prevention, an example would be attempting to prevent the seronegative partner acquiring HSV-2 in monogamous couples discordant for HSV-2 infection. Therapeutic trials of postinfective immunisation have used subjects with frequent re-activation of genital HSV infection.
Live attenuated virus vaccines
Attempts to produce 'attenuated' vaccines by serial passage have not led to candidate vaccines: there were concerns over stability and safety as well as likely efficacy. Several candidate HSV vaccines were produced by targeted genetic modification of supposed ‘virulence’ genes. Such vaccines were the R-70-20 vaccine which was a hybrid between HSV-1 and HSV-2 with deleted sequences – this was found to be too far attenuated and poorly immunogenic in phase I trials7, but a later vaccine of this type (ROV9395, Aviron) is in development8. An alternative approach has been to make virus capable of limited, or a single round of, replication by deletion of genes essential for replication. An example is the HSV-2 candidate vaccine virus deleted for the glycoprotein gH, which is essential for infectivity. The gH-deleted virus is grown on a complementing cell line which expresses gH: this results in virions which contain gH and are, therefore infective, but which cannot make further gH (lacking the gene) and are thus incapable of further replication. These have been termed disabled infectious single cycle (DISC) vaccines9, and been shown to be immunogenic in phase I trials (Cantab Pharmaceuticals). Another analogous replication-impaired HSV (AVANT) has also been tested in animals10.
Thus, at present, the glycoprotein subunit vaccines with newer adjuvants (some directed at inducing better mucosal immunity11) and the replication-impaired viruses are thought by most in the field to represent the best prospect for developing a vaccine. However, this goal is still some way off. The lack of definite correlates of protective immunity which can be used as end-points in phase I trials, and the difficulty and expense of mounting phase III trials for prevention of genital HSV infection, tend to deter manufacturers from entering the field (see elsewhere for reviews2,12,13).
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Vaccination against varicella-zoster virus (VZV) |
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Disease caused by VZV Primary infection with varicella-zoster virus (VZV) causes chickenpox, a generalized vesicular rash with fever and malaise. In children, chickenpox is common but serious complications are rare. In adults, primary infection can be more severe including pneumonitis. When chickenpox occurs during pregnancy, intra-uterine infection can lead to serious congenital malformations (8–10 cases of congenital varicella syndrome annually in the UK) or neonatal chickenpox14. In immunocompromised individuals, primary infection often leads to severe disease including encephalitis, hepatitis and pneumonitis. In England and Wales, approximately 270,000 cases of primary infection occur each year, and result in 20–25 deaths per year predominantly in adults15.
Upon primary infection, VZV establishes latent infection in neurons of sensory ganglia. Subsequent re-activation and migration of infectious virions along sensory neurons leads to zoster, a vesicular rash typically confined to a dermatomal distribution. The incidence of zoster increases with age, as does the occurrence of post-herpetic neuralgia16. Re-activation involving the eye may causing keratitis, uveitis or retinal necrosis. Less commonly, re-activation may lead to cranial nerve palsies, myelitis and cerebral vasculitis. In immunocompromised individuals, re-activation may lead to disseminated infection.
Vaccines against VZV VZV is the only herpes virus for which there is an effective vaccine on the market. The live attenuated vaccine was developed from the wild-type Oka strain of VZV by serial passage in cell culture. In humans, the vaccine strain establishes persistent infection and upon re-activation can cause zoster. Several countries including the US now have programmes of universal vaccination of healthy children. Currently, no vaccine is licensed for use in the UK, but Oka vaccine is available on a named patient basis for immunocompromised individuals such as children with leukaemia. Children aged 12 months to 12 years receive one dose of vaccine by subcutaneous injection, after which over 95% show seroconversion. Because of age-related decreases in the rates of seroconversion, older children and adults receive two doses 4–8 weeks apart. In addition to induction of anti-VZV antibody, the vaccine stimulates VZV-specific CD4+ and CD8+ T lymphocyte responses that recognize the VZV immediate early protein IE62 and glycoproteins gpI, gpIV and gpV: in vaccinated adults, the T lymphocyte responses against IE62 and gpIV persist for at least 4 years after vaccination and are of similar magnitude to the T lymphocyte responses generated in response to natural VZV infection17. The vaccine is generally well tolerated. The most frequent adverse effects are pain or swelling of the injection site (19%), fever (15%) and rashes that include mild generalized chickenpox-like rash (3%) and local injection site vesicular rash (3%).
Vaccine-induced protection against chickenpox in healthy children
In the randomised, double-blind, placebo-controlled trial of varicella vaccine in healthy children, 914 susceptible children aged 12 months to 14 years received vaccine (n = 468) or placebo (n = 446). During 9 months of follow-up, no cases of varicella occurred in the vaccine recipients, while 39 cases of varicella occurred in those who received placebo18. During subsequent follow-up of the trial participants for 7 years, 95% of the vaccine recipients remained free of varicella19. In this trial, the vaccine contained 17,000 plaque-forming units (pfu) per dose, whereas the vaccine that was subsequently licenced contains 3000–9000 pfu. Subsequent observational studies have confirmed that in healthy children the licensed vaccine confers a high level of protection against chickenpox caused by wild-type VZV. In a case-control study of the vaccine in the US, varicella vaccine prevented chickenpox in 85% of vaccinated children, with 97% protection against moderately-severe or severe disease20. Similarly, during follow-up of vaccine recipients who were exposed to VZV, in only 2 out of 100 exposures did vaccine recipients develop chickenpox21. Overall, in vaccinated individuals, breakthrough chickenpox caused by wild-type VZV occurs in 2–3% each year, but the disease is usually clinically mild22. Susceptibility to breakthrough chickenpox is inversely related to the concentration of anti-VZV antibody at 6 weeks after vaccination23.
Because large numbers of vaccine recipients have not yet been followed up for sufficient lengths of time, the duration of vaccine-induced protection remains unclear, and it is not known whether booster doses of vaccine will be required in future. In some follow-up studies, anti-VZV antibody declined to undetectable levels in 5% of the cohort24, while in others anti-VZV antibody was maintained for up to 20 years21. Longitudinal analysis of the titres of anti-VZV antibody in individual vaccine recipients has shown that asymptomatic 4-fold increases in titre occurred in 2–9% per year in those with higher baseline titres and in 11–22% per year of those with lower baseline titres. This boosting of anti-VZV antibody is likely to reflect exposure to VZV, but whether this was exposure to exogenous wild-type VZV, exogenous vaccine strain from another recently vaccinated child, or sub-clinical endogenous re-activation of vaccine strain remains unclear23. Because periodic subclinical exposure to wild-type VZV during annual epidemics may contribute to the maintenance and boosting of immune responses, the duration of protection induced by the vaccine alone will only become clear when chickenpox epidemics no longer occur. If vaccine-induced immune responses were to decrease with time, vaccinated individuals might become increasingly susceptible and acquire breakthrough chickenpox in later life.
Zoster due to re-activation of the vaccine strain
The incidence of zoster caused by wild-type VZV is low in healthy children but is higher in immunosuppressed children. Studies of children with leukaemia indicate that wild-type VZV re-activates more frequently than the vaccine strain: among children with leukaemia in remission, those who had a past history of natural chickenpox had a higher incidence of zoster (15 of 96 children) than those who received 1 or 2 doses of the live attenuated vaccine (4 of 96 children)25.
From observational studies to date, the incidence of zoster in healthy children who have received the vaccine appears to be as low as in those who have a past history of natural chickenpox. Further long-term follow-up of healthy individuals who have been vaccinated as children or as adults will be necessary to determine the incidence of zoster due to re-activation of the vaccine strain with increasing age.
Postinfective immunisation for prevention of zoster
Trials are in progress to assess whether postinfective immunisation with the Oka vaccine can diminish the incidence of zoster in those over the age of 50 years: it has already been shown to boost pre-existing cell-mediated immunity to VZV in this age group.
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Vaccination against human cytomegalovirus (HCMV) |
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Disease caused by HCMV Following primary infection, HCMV persists for life as a latent infection with periodic asymptomatic excretion of virus in saliva, breast milk, urine, semen and cervical secretions. In non-industrialised countries, HCMV is usually acquired in childhood and seropositivity approaches 100%, whereas in industrialised countries seropositivity increases with age reaching about 50% in adulthood. In childhood, HCMV is acquired from breast milk or contact with other infected children excreting virus in their saliva or urine: studies in day nurseries have shown transmission between children as well as to susceptible adult carers. Later, sexual transmission becomes a major route of infection: seroprevalence approaches 100% in homosexual men and sex workers. In hospital patients, blood and blood products can transmit HCMV: transfusion recipients who are at risk of serious HCMV disease now usually receive blood from screened seronegative donors to prevent transmission. Solid organ and bone marrow transplants from seropositive donors can transmit HCMV, and produce particularly severe disease (such as pneumonitis and other organ disease) in seronegative recipients. In the US, HCMV infection complicates about 2800 organ transplant recipients per year with a 6% mortality rate. HCMV retinitis occurs in about 25% of patients with untreated advanced HIV infection.
However, the most important justification for a vaccine is to prevent congenital HCMV disease. Recent data from the US estimate that 40,000 infants per year are born with congenital HCMV infection of whom 15% will develop neurologic sequelae, and there is a 1% mortality rate12. Fetal infection is more severe when a seronegative mother acquires primary infection in early pregnancy: the risk of symptomatic congenital infection from re-activation of maternal HCMV in pregnancy is lower, although not absent, as pre-existing maternal immunity limits spread to the fetus.
Vaccines against HCMV There is a compelling argument that a safe and effective vaccine administered during puberty to both males and females would be of major benefit. A live attenuated whole virus vaccine produced by extensive passage in vitro of a clinical isolate was first reported in 1975. Initial trials in renal transplant recipients suggested that vaccination attenuated the disease course26. However, when this vaccine was given to HCMV seronegative mothers of seropositive children, the incidence of primary infection was similar to the placebo control group. It was noted that neutralizing antibody titres were 10–20-fold lower in the vaccine groups as compared to natural wild-type infection27. Recent analysis of the genetic differences between clinical HCMV isolates and the attenuated Towne strain28 identified 15 kb of DNA containing open reading frames which are absent from Towne. It is likely that these differences give rise to the alteration in virulence. Chimeric Towne strains containing regions of the missing DNA from clinical strains are being constructed in an attempt to avoid the presumed overattenuation of Towne and increase its immunogenicity.
A range of alternate strategies which do not utilize whole live virus are also under investigation. A subunit vaccine based on glycoprotein B (gB) adjuvanted with MF59 (an oil emulsion) has been used in a phase I trial and was shown to induce neutralizing antibodies with no serious side-effects29. However, data from solid organ and bone marrow transplant patients suggest that cell-mediated immunity is also important in the control of HCMV infection30. Detailed analysis of T-cell responses in normal healthy HCMV seropositive individuals has identified the major tegument protein pp65 and the immediate early protein IE1 as immunodominant T-cell antigens for both CD8+ and CD4+ T-cells31–35. It is likely that there are also subdominant responses to other HCMV proteins33. The high frequency CD8+ cytotoxic T lymphocyte (CTL) responses directed against pp65 and IE1 in most healthy virus carriers have led to more recent efforts to construct HCMV vaccines capable of inducing such CTL responses.
HCMV infection of primary fibroblasts in vitro not only leads to the production of infectious virus but also to the formation of enveloped non-infectious particles called dense bodies, which contain pp65 and gB. Vaccination of mice with purified HCMV dense bodies led to the production of both neutralizing antibodies and CD4+/CD8+ T-cell-mediated immunity, and it has been suggested that dense bodies might form the basis of a non-infectious vaccine36. Vaccination of mice with the murine CMV (MCMV) homologue of pp65, as plasmid DNA, resulted in protection from challenge (MCMV is a distinct virus from HCMV but has somewhat similar biology).
Recombinant attenuated canarypox virus vectors expressing gB (ALVAC-CMV gB) and pp65 (ALVAC-CMV pp65) have been constructed and tested for their ability to induce neutralizing antibodies and CTL responses in humans. Three doses of ALVAC-CMV(gB) induced only low levels of neutralizing antibody; however, two doses of ALVAC-CMV(gB) followed by a dose of Towne did induce high levels of neutralizing antibody37. In a separate study, two doses of ALVAC-CMV (pp65) were shown to induce CTL responses in all subjects and these responses were still present at 26 months' post-vaccination38. DNA plasmids encoding gB and pp65 have also been used to vaccinate mice: anti-gB and anti-pp65 antibodies were induced as well as pp65-specific CTL responses39. The use of minimal CD8+ T-cell epitopes derived from immunodominant viral proteins (e.g. pp65) and administered in conjunction with strong T-cell helper epitopes (e.g. from tetanus toxoid) has also been proposed. Administration of these mixed peptides to mice transgenic for human HLA A*0201 and HLA-DR1 generated strong pp65-specific CTL responses40. A more extensive review of HCMV vaccines has recently been published41.
Adoptive transfer of T-cells and passive immunisation Passive administration of antibody to patients with HCMV disease is of limited utility in preventing or treating HCMV disease. However, considerable effort has also been invested in the ex vivo generation and subsequent adoptive transfer of HCMV-specific CD8+ T-cell clones into patients, in order to restore immunity in marrow transplant recipients following haematopoietic stem cell transplantation (SCT). In a phase I study, pp65-specific CD8+ clones were successfully transferred to SCT recipients, but their frequency declined over a period of weeks in those patients that did not reconstitute CD4+ T helper cell responses42. A soluble recombinant chimeric IE1–pp65 protein has recently been constructed and shown to stimulate both CD4+ and CD8+ T-cells ex vivo43: the cells generated using this reagent may provide for a longer lasting reconstitution of BMT patients. These approaches give some insight into the responses that might be required of an effective vaccine.
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Vaccination against Epstein-Barr virus (EBV) |
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Disease caused by EBV Upon primary EBV infection, about 50% of adults develop significant signs of clinical infectious mononucleosis (IM): it has been suggested that this may relate to virus load44 and that a vaccine might only have to reduce the viral load in order to reduce significantly the incidence of clinical IM. However, it is the human malignancies with which EBV is associated that provide the principal justification for a vaccine: principally naso-pharyngeal carcinoma, Burkitt's lymphoma and post-transplant lymphoproliferative disease (and possibly Hodgkin's disease). Cell lines derived from these tumours display three distinct patterns of latency defined by specific patterns of viral gene expression.
Vaccines against EBV As with HCMV, there is now a reasonable consensus as to which viral proteins are targets for neutralizing antibodies and cytotoxic CD8+ T-cell-mediated immunity in normal EBV carriers, and this provides a rational basis for the design of a vaccine.
Antibodies to the viral glycoprotein gp350 are neutralizing: gp350 as a subunit vaccine or expressed from recombinant viral vectors conferred protection in a model of EBV-induced B-cell lymphoma in cotton-top tamarins45. A live recombinant vaccinia virus expressing the major EBV membrane antigen, LMP (latent membrane protein)-1, from the BNLF-1 open reading frame (gp 220–340) was constructed and tested in human populations. All unvaccinated control infants became naturally infected; however, only 3/9 vaccinated infants became infected after 16 months46.
Antiviral CTL responses are critical for the control of established EBV infection. This is dramatically demonstrated in patients who are immunosuppressed following bone marrow or solid organ transplantation, who are at increased risk of developing B-cell lymphoproliferative disorders (BLPD). As do infected B-cells during acute IM, these cells express a wide range of viral antigens. Complete regression of BLPD has been achieved using adoptive transfer of EBV-specific CTL, after their ex vivo activation and expansion47. The design of peptide-based vaccines to induce CTL immunity in normal EBV seronegative individuals has been reviewed recently48.
It may prove much more difficult to develop vaccines against nasopharyngeal carcinoma (NPC), Hodgkin's disease which has a latency type II pattern, and Burkitt's lymphoma with a latency type III pattern. These tumours express only a limited number of viral gene products and develop many years after primary EBV infection. Hodgkin's disease cells express EBV LMP-2: there is little natural CTL activity generated against this protein, but it may be possible to boost the CTL response. It has been demonstrated that dendritic cells transduced with LMP-2 vectors can induce specific CTL in vitro49. Burkitt's lymphoma poses an additional hurdle to the T-cell response in that the tumour cells have reduced surface MHC class I and only express EBNA (EBV nuclear antigen)-1, which can prevent its own presentation by MHC class I. It has been suggested that Burkitt's lymphoma might be targeted by restoring MHC class I antigen presentation in the tumour cells and a number of approaches have been investigated (reviewed by Khanna et al50).
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Vaccination against human herpes viruses 6–8 (HHV-6, HHV-7, HHV-8) |
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HHV-6 (and to a lesser extent HHV-7) causes the childhood exanthem roseola, and is associated with infantile febrile convulsions. It seems unlikely there will be a case for the development of a vaccine because infants may be infected so early in life, while they still have maternal antibody.
HHV-8 is the most recently isolated of the human herpes viruses. Its sero-epidemiology, biology, and disease associations are still being analysed, but HHV-8 is clearly closely associated with Kaposi's sarcoma (a tumour long suspected of having a viral aetiology), with primary effusion lymphoma and with Castleman's disease. Reported associations with multiple myeloma and other cancers are unconfirmed. Given the evolving knowledge of the epidemiology and disease associations of HHV-8, no preventive measures are currently used. There is no vaccine, but there could be a case for one in future.
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Vaccination for other persistent DNA viruses |
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Papilloma viruses There is considerable interest in vaccine development against these small persistent DNA viruses, given their association with important epithelial malignancies (cervical, anogenital and skin cancers). This topic is beyond the scope of this chapter and is reviewed elsewhere51,52.
Papova viruses (JC and BK) There is no impetus to develop vaccines against these ubiquitous viruses which are only associated with uncommon disease in immunosuppressed subjects (JC with progressive multifocal leuco-encephalopathy, and BK with a transplant nephropathy and ureteric stenosis in renal transplant recipients).
Adenoviruses and parvovirus Adenoviruses and parvovirus are DNA viruses which may sometimes cause persistent infection, but for which there are no generally available vaccines (vaccines have been developed against some adenoviruses for use in the military).
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Footnotes |
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Correspondence to: Prof. J G P Sissons, Department of Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
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