Table 3.

Selected clinical trials of VACV-derived smallpox vaccines used as vectors for other infectious diseases or cancer.

Vaccine	Subjects Enrolled	Findings	AEs/SAEs	Reference
MVA and FPV expressing HIV-1 env, gag, tat, rev, nef, RT (PACTG P1059)	20 HIV-infected young adults	Safe and well-tolerated; increased HIV-1 specific CD4+ and CD8+ T cell responses vs baseline	Injection site reactions common; no SAEs or AEs related to product	[145]
MVA expressing HIV-1 nef	14 HIV-infected, remotedly VACV-vaccinated men	Increased total CD4+ and CD8+ T cell counts; 9 of 14 had ELISPOT responses to nef insert; MVA-specific antibodies induced	Local reactogenicity common, systemic reactogenicity seen; no SAEs	[146]
VACV and FPV expressing PSA and co-stimulatory molecules (PROSTAVAC-VF)	125 men with castration-resistant metastatic prostate cancer	44% reduction in deaths over 3 years and 8.5 months longer median survival	Injection site reactions common; one case of TTP and MI graded as “possibly related”	[110]
NYVAC-C (vP2010) expressing HIV-1 clade C gag, pol, env, nef	24 healthy volunteers (EV01)	50% ELISPOT responses to HIV-1 peptides (EV01)	Mild to moderate reactogenicity; no SAEs; one subject with high ALT after first DNA vaccination (EV02	[134,136–138]
	40 healthy volunteers (EV02)	83% ELISPOT responses to HIV-1 peptides in DNA-NYVAC group vs 35% in NYVAC alone; polyfunctional HIV-1 specific CD4+ and CD8+ T cells induced by DNA-NYVAC(EV02)
	147 healthy volunteers (EV03/ANRS Vac20)	91% ELISPOT response with 3 doses of DNA prime vs 80% with 2 doses; increased breadth of responses as well	Study pending	clinicaltrials.gov NCT00490074
NYVAC-B (vP2009) expressing HIV-1 clade B gp120 gag-pol-nef	80 healthy volunteers	HVTN 078 study ongoing	Not yet available	clinicaltrials.gov NCT00961883
MVA expressing HIV-1 clade B gag, protease, RT, env (MVA/HIV62)	120 healthy volunteers (HVTN 065)	T cell responses higher in DNA prime/MVA boost; binding antibodies higher in MVA alone group	Mild to moderate local and systemic reactogenicity	clinicaltrials.gov NCT00301184 [117]
	300 healthy volunteers (HVTN 205)	HVTN 205 study ongoing	Not yet available	clinicaltrials.gov NCT00820846
MVA expressing CD8+ T cell epitopes and truncated gag derived from HIV-1 clade A (MVA.HIVA)	35 healthy volunteers	Immunogenic for HIV-derived insert in majority of MVA recipients	Local reactogenicity common; one SAE (possible concomitant viral gastroenteritis)	[111–115]
	119 healthy volunteers	Only 10% of vaccines responsed to HIVA insert	Local reactogenicity common, no related SAEs
	24 healthy volunteers	4 of 8 MVA vaccinees and 8 of 8 DNA/MVA vaccinees developed T cell responses (mostly CD4+)	Not reported
MVA expressing HIV-1 clade C gag-RT-tat-nef and truncated gp160 (SAAVI-MVA-C)	48 healthy volunteers	HVTN 073 study ongoing	Study ongoing	clinicaltrials.gov NCT00574600
MVA expressing HIV-1 clade C env, gag, tat, rev, nef, and RT	32 healthy volunteers	82% and 100% ELISPOT and 91% and 100% binding antibody response rates in low- vs high-dose MVA recipients	Local reactogenicity higher in high-dose group; no SAEs, no cardiac events	[147]
MVA expressing env, gag, pol derived from HIV-1 CRF01_AE	48 healthy volunteers	Dose and route dependent cellular and humoral immune responses with 108 IM highest	Local reactogenicity more common with ID and higher dose; no related SAEs	[148]
MVA expressing 5T4 (TroVax)	19 patients with metastatic colorectal cancer undergoing chemotherapy	1/19 had complete remission, 6/19 had partial remissions, 5/19 had stable disease	No related SAEs, no increase in chemotherapy-related side effects	[123,149,150]
	28 patients with metastatic renal cancer	1 patient had partial remission; 14 had stable disease; addition of IFNα to MVA-5T4 increased antibody responses, but decreased cellular immune responses	No related SAEs
	733 patients with metastatic renal cancer	No difference in survival between vaccinees and placebo recipients; trend toward enhanced survival with higher antibody responses to 5T4	No difference in AEs/SAEs between vaccinees and placebo recipients
MVA expressing HPV E2 (MVA-E2)	54 women with CIN II or III	20/34 vaccinees with complete resolution; 16/20 response rate to excision in controls, but 3 relapsed within 1 year	Mild AEs reported	[151,152]
	50 men with intra-urethral flat condylomata	28/30 vaccinees with complete resolution; 13/20 controls responded to 5-FU, but 3 relapsed within 1 year	Mild AEs commonly reported
MVA expressing epitopes derived from melanoma antigens (MVA-Mel3)	14 HLA-A2+ patients with resected melanoma at risk of recurrence	7/13 vaccinees had an epitope-specific tetramer response	Mild local and systemic reactogenicity common	[128,129]
	41 HLA-A2+ patients with unresectable melanoma	71% of vaccinees had Melan-A-specific tetramer responses which correlated with increased median survival; 21% had some degree of clinical response	Dose-dependent mild-to-moderate local and systemic reactogenicity seemed to decrease with subsequent doses; one possible allergic reaction noted
MVA expressing M. tb antigen 85A (MVA-85A)	42 healthy volunteers	Highly immunogenic in BCG-naïve and BCG-vaccinated recipients	Local reactogenicity very common; systemic reactogenicity common	[118,119]
MVA and FPV expressing malaria antigens ME-TRAP	405 children in coastal Kenya	No protection against malaria	No difference in AEs/SAEs between vaccinees and controls; no SAEs related to product	[121,122]
MVA expressing influenza A NP and M1	28 healthy adults	2.5 to 11 fold increase in T cell responses	Local reactogenicity more common with ID administration; systemic reactogenicity higher with high dose IM administration	[153]
MVA expressing EBV EBNA-1 and LMP2 (MVA-EBNA1/LMP2)	37 patients with treated nasopharyngeal cancer and residual EBV DNA load	Study enrolling	Not yet available	clinicaltrials.gov NCT01094405
VACV and FPV expressing CEA, MUC-1, and co-stimulatory molecules (PANVAC-VF)	48 patients with metastatic breast cancer	NCI-05-C-0229 study enrolling	Not yet available	[154] clinicaltrials.gov NCT00179309

Abbreviations: VACV – vaccinia virus; HVTN – HIV Vaccine Trial Network; PACTG – Pediatric AIDS Clinical Trial Group; PSA – prostate-specific antigen; TTP – thrombogenic thrombocytopenic purpura; FPV – fowlpoxvirus; ALT – alanine aminotransferase; ANRS - Agence nationale de recherches sur le sida et les hépatites virales; SAAVI – South African AIDS Vaccine Initiative; HPV – human papillomavirus; CIN – cervical intra-epithelial neoplasia; 5-FU – 5-fluorouracil; M. tb – Mycobacterium tuberculosis; BCG – bacille Calmette-Guérin; ME-TRAP – multiple epitope string and thrombospondin related adhesion protein; NP – nucleoprotein; M1 – influenza matrix protein 1; ID – intradermal; IM – intramuscular; CEA – y antigen; MUC-1 – mucin-1