• Vaccine Name: NYVAC
• Target Pathogen: Variola virus
• Target Disease: Smallpox
• Vaccine Ontology ID: VO_0004093
• Type: Replication defective virus
• Preparation: NYVAC was derived from the Copenhagen strain and developed by selective deletion of 18 open reading frames (ORFs) (Parrino et al., 2006).
• Virulence: (Belyakov et al., 2003; Edghill-Smith et al., 2003)
• Description: Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4+ T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus (HIV) type 1 infection, that a prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent poxvirus (Edghill-Smith et al., 2003).

Mouse Response

• Host Strain: BALB/c, B cell-deficient, and CD1 KO–/– mice
• Vaccination Protocol: Female BALB/c mice (6–10 weeks old, purchased from Frederick Cancer Research Facility, Frederick, MD), B cell-deficient (Taconic Farms), and CD1 KO-/- (CD1KO, from M. Grusby) mice were innoculated with NYVAC at doses from 10^3 to 10^7 pfu. For comparison, and as a positive control, immunization with Wyeth human vaccine strain of vaccinia virus was given by tail scratch (corresponding to skin scratch used for human vaccination). One month after immunization, mice were challenged with 10^6 pfu of WR by intranasal (i.n.) inoculation (Belyakov et al., 2003).
• Persistence: (Belyakov et al., 2003)
• Side Effects: None were mentioned. Replication-defective strains might be valuable as a preliminary immunization to reduce the risk of serious adverse ffects of conventional smallpox vaccination (Belyakov et al., 2003).
• Efficacy: Protection at most doses of NYVAC given i.m. was roughly comparable to that produced by the corresponding doses of MVA given i.m., and no statistically significant difference was detected. It was found that i.m. injection with MVA induced protection of immunized animals in a dose-dependent manner. A dose of 10^7 pfu of MVA given i.m. induced complete protection against challenge with WR (Belyakov et al., 2003).
• Description: At sufficient doses, the protection provided by modified NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus i.n. challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus (Belyakov et al., 2003).

Monkey Response

• Host Strain: Indian rhesus macaques
• Vaccination Protocol: Twenty-five monkeys were enrolled: 6 of the macaques were immunocompetent (groups 1 and 2), and macaques in group 1 were vaccinia naive. Macaques in group 2 had been exposed previously to the attenuated nef- SIVmac239 strain. They were immunized with a single inoculation of NYVAC 1 month before Dryvax vaccination. Group 3 included 7 macaques, 3 that had been infected with the chimeric SHIV 89.6 PD strain for 8 months, 3 that had been infected with the SIVmac251 strain for 12 months, and 1 that had been infected with the nef- SIVmac239 strain for 32 months. Four macaques (group 5) that, at first, had been infected with the same SIVmac251 strain and that subsequently were vaccinated with 3 inoculations of NYVAC, at weeks 10, 19, and 23 after infection (for macaques 480, 644, and H684) or at weeks 42, 48, and 54 after infection (for macaque 3143), were used. The overall time of SIVmac251 infection was 41 months for macaques 480 and 644 and 25 months for macaques H684 and 3143. Four macaques had been infected with SHIV 89.6 PD for 12 months. They were vaccinated with 3 inoculations of NYVAC (10^8 pfu) 6 weeks apart and were challenged with Dryvax 6 months after the final NYVAC immunization. All 25 macaques were vaccinated with Dryvax at the same dose at the times indicated. In brief, the bifurcated needle was immersed in the vaccine suspension and was used to poke the skin 15 consecutive times, in accordance with US Food and Drug Administration (FDA) guidelines. The lesions that developed after smallpox vaccination were photographed every 2 days and were imaged by manually defining the topographic contours of the affected skin (Edghill-Smith et al., 2003).
• Persistence: The immunocompromised macaques were vaccinated with NYVAC at 6 months to a maximum of 36 months before Dryvax challenge, suggesting that this vaccine is able to induce lasting immune responses even as CD4+ helper T cells are progressively depleted. However, the lag between NYVAC and Dryvax vaccinations appears to be important (Edghill-Smith et al., 2003).
• Side Effects: The prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination (Edghill-Smith et al., 2003).
• Efficacy: The prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and highlights the importance of neutralizing antibodies in protection against virulent poxvirus (Edghill-Smith et al., 2003).
• Description: The replication competence of live vaccines, such as the only currently available smallpox vaccine, Dryvax, may pose safety concerns when injected in individuals with congenital, acquired, or iatrogenic immunodeficiency. Because the number of patients with immunodeficiency has increased worldwide as a result of the HIV-1 epidemic, the increase in the number of organ transplants, and aggressive chemotherapy in patients with cancer, the risks associated with Dryvax vaccination may affect a larger portion of the population than before. It has been hypothesized that immunization of immunocompromised individuals, with highly attenuated poxviruses, may ameliorate the clinical outcome of Dryvax vaccination. In macaques with modest to severe depletion of CD4+ T cells, it was tested whether immunization with NYVAC before or after infection with simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV) would increase the safety of Dryvax vaccination. NYVAC was shown to be safer in severely immunocompromised macaques and that NYVAC priming resulted in a faster resolution of Dryvax-induced lesions in both healthy and immunocompromised macaques (Edghill-Smith et al., 2003).