Clinical Experience

A. Smallpox Vaccination

Extensive clinical experience exists with vaccinia virus as a vaccine for the eradication of smallpox. The most common commercial preparation used in the United States was the Wyeth Dryvax (101). It is the only vaccine available today. The virus was produced by infection of live calves by dermal scarification, followed by physical scraping of the skin. Future vaccines will be produced on cell lines, and ongoing trials are comparing strains for safety and efficacy (56). The vaccine is delivered by scarification of the skin. The lyophilized virus is reconstituted and spread on the skin. A scarification needle is then used to penetrate the dermis through the vaccinia coat in multiple places. Effective vaccination is indicated by the development of pustules 6 to 10 days after vaccination. The pustules represent replicating vaccinia within the dermis. Live virus can be recovered from the pustules from days 3 through 14 after vaccination. There is a direct relationship between the intensity and extent of virus multiplication in the skin and the magnitude and duration of antibody response. The immune protection seems to last a lifetime, including both circulating antibodies and memory T cells (102). The current recommendation, however, is to be boosted with vaccinia every 10 years.

Adverse events occurred in about 1250 per million vaccinations, as described above, including vaccinia necrosum, vaccinia-associated encephalitis, and eczema vaccinatum (102). Aggressive dermal replication occurred almost exclusively in patients who were T cell immunodeficient. The majority of deaths occurred in infants who suffered postvaccinal encephalitis. The risk of complications increased with the more virulent strains of virus used in Austria and Denmark. Despite worldwide use of this live virus vaccine, no reported adverse events related to mutation of the virus to a more aggressive phenotype was ever reported. No viral-induced tumor formation has been reported. Overall, the virus is remarkably safe for use in humans, despite controlled viral replication in the skin of a potentially destructive virus.

B. Other Vaccines

After proven success as a vaccine responsible for the elimination of endemic smallpox in the world, the obvious leap toward using vaccinia as a vaccine for other indications was made, and vaccinia was engineered to express antigens from other infectious agents. Likewise, as tumor antigens were recognized and defined, vaccinia was used as a cancer vaccine. The size of the vector allows for flexibility in engineering, such that immune-enhancing genes and antigen genes can be recombined together into the genome. In general, these approaches do not rely on targeting of any specific tissues and may not require viral replication, rather they are designed to take advantage of the immune stimulatory effects of the complex viral particle and the efficient transcriptional machinery of the virus. For safety considerations, nonreplicating vaccinia mutants were developed. The known inflammatory response to the vector combined with tumor antigens and immunostim-ulatory molecules holds promise for cancer therapy. The potential seems great, but controversy exists as to whether complex immunogenic viruses such as vaccinia may be less effective as vaccine vectors against proteins foreign to the virus.

Vaccinia virus has been used in multiple clinical trials as vaccines for treatment of a variety of tumors as well as treatment of infectious diseases such as rabies and HIV (Table 3). Vaccinia virus has been delivered as subcutaneous, intramuscular, intratumoral, and intravesical (bladder) injections in clinical immunotherapy trials without significant vector-related toxicity (60,103,104). Doses of up to 109 plaque-forming units (pfu) have been delivered safely. Intravenous injection of fowlpox virus has been performed with no significant toxicity; however, this species does not replicate in human cells. No systemic injection of a replicating vaccinia virus has been performed in human trials.

Allogeneic cell lysate vaccines incorporating vaccinia virus have been explored clinically. In these studies, vaccinia was not used as a vector, but as an immunogen. The virus was not replication competent. A phase 3 randomized, doubleblind, multi-institutional trial of an allogeneic vaccinia virus-augmented melanoma cell lysate (VMO) vaccine was performed with 250 patients from 11 centers (105). A 10% sur vival advantage to VMO-treated patients was detected; however, this was not statistically significant. Hersey et al. in Australia also reported an improved survival in patients treated with an allogeneic vaccinia melanoma cell lysate vaccine (105,106). In many of these trials, DTH response and development of antibodies to tumor antigens correlates with disease-free survival. No vaccinia pathogenicity was observed.

Eder et al. reported a phase I trial of vaccinia expressing prostate-specific antigen in prostate cancer patients (108). The virus was delivered intradermally every 4 weeks for 3 doses. No significant toxicities were related to the virus, which was a Wyeth strain. A cutaneous reaction consistent with viral replication was seen in all patients treated with 2.65 x 107 pfu vaccinia or greater. Fourteen of 19 patients continued to demonstrate cutaneous replication after the third dose. Several patients developed T cell immune responses associated with prolonged stabilization of their cancer. Vaccinia expressing carcinoembryonic antigen (CEA) has been studied clinically as a priming vaccine followed by a boost with avipox expressing CEA(109).Thisregimenconsistedof 1 x 107pfuWyeth strain vaccinia injected intradermally, and it was well tolerated. Specific T cell immune responses were generated without clinical responses. A good example of the utility of vaccinia as an immune vector is the development of rV-CEA TRICOM by Greiner et al. (110). This vaccinia expresses a triad of costimu-latory molecules: B7.1, ICAM-1, andLFA-3, along with CEA for a vaccine against CEA expressing cancers. This vector demonstrated encouraging preclinical results and is now in clinical trials. Numerous other trials are in varying stages of accrual using vaccinia to express different tumor antigens.

C. Replication Selective Vaccinia ''Oncolytic Therapy''

The extent of experience with vaccinia over the years and its proven safety record should lead to acceptance of exploration

Table 3 Recombinant Vaccinia Virus Used in Clinical Trials

First author

Vector

Results

Mastrangelo (60)

Vaccinia-GmCSF

Regression of injected lesions

Marshall (109)

Vaccinia-CEA

No clinical response

Mukherjee (114)

Vaccinia-IL-2

No clinical response

Eder (108)

Vaccinia-PSA

Stabilization of PSA levels

Sanda (126)

Vaccinia-PSA

Stabilization of PSA levels

Conry (127)

Vaccinia-CEA

No clinical response

Tsang (128)

Vaccinia-CEA

No clinical response

Graham (129)

HIVAC-le (gp160)

HIV immunity in healthy controls

Adams (130)

Vaccinia-HPV

Responses in cervical cancer

Kanesa-thasan (131)

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