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Vaccine Detail

ACAM1000
Vaccine Information
  • Vaccine Name: ACAM1000
  • Target Pathogen: Variola virus
  • Target Disease: Smallpox
  • Vaccine Ontology ID: VO_0004089
  • Type: Replication competent virus
  • Preparation: ACAM1000 was purified from Dryvax by sequential plaque selection to isolate clone (Weltzin et al., 2003).
  • Virulence: By most measures, ACAM 1000 is less virulent than Dryvax, the existing human smallpox vaccine (Weltzin et al., 2003).
  • Description: Dryvax supplies could be stretched by dilution. As vaccine supplies would still be insufficient, a new vaccine derived from Dryvax that is suitable for modern manufacture in cell culture at a large scale must be developed and clinically tested. The new vaccine forms the basis for the United States government's strategic vaccine stockpile for biodefense, and other countries are taking a similar course of action (Weltzin et al., 2003).
    Clinical trials have been conducted using the NYCBH-derived ACAM1000 vaccinia virus-based vaccines. ACAM1000 was similar to Dryvax in its ability to induce immune responses and in reactogenicity in phase I trials (Parrino et al., 2006).
Host Response

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: The following lethal intranasal vaccinia (strain WR) challenge model was used to evaluate protective immunization by vaccinia clones in mice. Mice were immunized by scarification with graded doses of ACAM1000 and then challenged by intranasal inoculation with 100 times the median lethal dose (LD50) of vaccinia-WR (Weltzin et al., 2003).
  • Persistence: In one mouse model, all sham-immunized animals died (average survival time [AST] = 5.2 d), whereas immunized mice all survived (3-5 weeks). Another mouse model involving IN challenge showed protection with minimal transient weight loss, while sham-immunized mice had severre weight loss and all died (AST = 12.6 d) (Weltzin et al., 2003).
  • Side Effects: transient weight loss (Weltzin et al., 2003)
  • Efficacy: All mice immunized with 7 or 8 log10 PFU/ml survived. At lower vaccine doses, survival was reduced in a dose-dependent manner. Body weight decreased 1−2 d after challenge but increased subsequently in mice receiving the highest doses of vaccine viruses. Protection by all clones was similar to that of Dryvax. The dose that protected 50% of mice from death (PD50) was 5.5 log10 PFU/ml for Dryvax (Weltzin et al., 2003).
  • Description: Vaccine candidates were purified from Dryvax either by sequential plaque selection to isolate clones or by passage at low multiplicity of infection (MOI) to isolate a polyclonal virus. The starting material was a pool of 30 vials (3,000 doses) of Dryvax from three different production lots. Six clones were isolated by three sequential rounds of plaque purification in MRC-5 cells (human lung fibroblast cell line). The clones were then amplified in fluid cultures to produce vaccine candidates. The polyclonal strain was produced by passage three times in MRC-5 cells at MOI 0.001 plaque-forming units (PFU)/cell. HindIII restriction endonuclease analysis was carried out on viral DNA isolated from the seven vaccine candidates and Dryvax. All DNA samples yielded digestion products corresponding to those of Dryvax, indicating that there were no major genetic rearrangements. Minor variations in the molecular weights of individual bands, such as band K of clone 3 and possibly the higher-molecular-weight bands of clone 2, were observed. Based on its attenuated phenotype in mice and similarity to Dryvax in other characteristics, clone 2 was selected as the best candidate for further development and was renamed ACAM1000 (Weltzin et al., 2003).

Monkey Response

  • Host Strain: Young adult rhesus monkeys.
  • Vaccination Protocol: Monkeys (six per group) were vaccinated by scarification using a bifurcated needle. All 18 monkeys developed typical primary cutaneous reactions. Neutralizing antibodies against both variola and vaccinia viruses were measured 30 d after vaccination (Weltzin et al., 2003).
  • Persistence: Neutralizing antibodies against both variola and vaccinia viruses were present at >30 d post-vaccination (Weltzin et al., 2003).
  • Side Effects: Dryvax can causes severe neurobiological illness and mortality via nonpurulent meningitis. ACAM 1000 can lead to mild edema and small areas of lymphoid infiltration (Weltzin et al., 2003).
  • Efficacy: Antibodies to variola at titers 1:40 were present in two of six monkeys inoculated with ACAM1000. Neutralizing antibodies to vaccinia virus appeared in five of six inoculated with ACAM1000 (titers, 1:10−40) (Weltzin et al., 2003).
  • Description: Vaccine candidates were purified from Dryvax either by sequential plaque selection to isolate clones or by passage at low multiplicity of infection (MOI) to isolate a polyclonal virus. The starting material was a pool of 30 vials (3,000 doses) of Dryvax from three different production lots. Six clones were isolated by three sequential rounds of plaque purification in MRC-5 cells. The clones were then amplified in fluid cultures to produce vaccine candidates at MRC-5 passage. The polyclonal strain was produced by passage three times in MRC-5 cells at MOI 0.001 plaque-forming units (PFU)/cell. HindIII restriction endonuclease analysis was carried out on viral DNA isolated from the seven vaccine candidates and Dryvax. All DNA samples yielded digestion products corresponding to those of Dryvax, indicating that there were no major genetic rearrangements. Minor variations in the molecular weights of individual bands, such as band K of clone 3 and possibly the higher-molecular-weight bands of clone 2, were observed. Based on its attenuated phenotype in mice and similarity to Dryvax in other characteristics, clone 2 was selected as the best candidate for further development and was renamed ACAM1000. This model was performed to confirm the immunogenicity of ACAM1000 that was observed in mice (Weltzin et al., 2003).

Human Response

  • Host Strain: Healthy adults 18-29 yrs.
  • Vaccination Protocol: ACAM1000 for clinical testing was produced at pilot lot scale (750,000 doses) according to current Good Manufacturing Practices. A randomized, double-blind clinical study was carried out under an Investigational New Drug application approved by the United States Food and Drug Administration to evaluate the safety, tolerability and immunogenicity of ACAM1000 in 60 healthy adults, without prior smallpox vaccination. On day 0, 30 eligible subjects received inoculation of ACAM1000 by 15 strokes of a bifurcated needle. The vaccine formulation contained 108 PFU/ml. Subjects took daily oral temperature, completed a symptom diary and returned to the clinic on days 3, 7, 10, 15, 30 and 45 and after 6 months for evaluation. The primary endpoint was the proportion of subjects developing a major cutaneous reaction ('take') on day 7 and/or day 10. The primary statistical method was a test of noninferiority of ACAM1000 to Dryvax intended to rule out a 20% difference in take rates. Based on a one-tailed test of noninferiority, with a significance level of 0.05 and power of 80%, and assuming that the common rate of major cutaneous reaction is 90%, 30 subjects per arm of the trial would be required to rule out an ACAM1000 rate of response of 70% or less. Secondary endpoints were neutralizing antibody and T cell responses on days 0 and 45. Peripheral blood mononuclear cells (PBMC) were evaluated by CTL, IFN-gamma ELISPOT and lymphoproliferation assays (Weltzin et al., 2003).
  • Persistence: Subjects took daily oral temperature, completed a symptom diary and returned to the clinic on days 3, 7, 10, 15, 30 and 45 and after 6 months for evaluation. It is expected to confer lifelong immunity (Weltzin et al., 2003).
  • Side Effects: No serious adverse events were reported, and no subject was withdrawn from the study because of an adverse event. All 60 subjects experienced at least one adverse event related to the local cutaneous infection with vaccinia virus. Minimal changes in body temperature were noted. Two subjects experienced atypical healing at the vaccination site. No cardiac adverse events occurred, despite recent reports of myopericarditis. The trial was not powered sufficiently to detect the rare serious adverse events associated with smallpox vaccines (Weltzin et al., 2003).
  • Efficacy: The rate of successful vaccination was 100% (30 of 30 subjects) for ACAM1000 and 97% (29 of 30 subjects) for Dryvax (Table 1). By the prescribed statistical test, ACAM1000 was not inferior in immunogenicity to Dryvax (P < 0.001) (Weltzin et al., 2003).

    T-cell memory to smallpox declines slowly over time, with a half-life of 8–15 years, whereas serum antibody responses (and B-cell memory) to smallpox are maintained essentially for life with little or no observable decline. The protection afforded by smallpox vaccination shows that >90% of vaccinees are protected against lethal smallpox (normally 30% mortality in unvaccinated individuals) for at least 60 years post-vaccination (Slifka, 2004).
  • Description: Dryvax supplies could be stretched by dilution. As vaccine supplies would still be insufficient, a new vaccine derived from Dryvax that is suitable for modern manufacture in cell culture at a large scale must be developed and clinically tested. Safety, tolerability and immunogenicity of ACAM1000 was evaluated based upon comparable results with Dryvax (Weltzin et al., 2003).
References
Parrino et al., 2006: Parrino J, Graham BS. Smallpox vaccines: Past, present, and future. The Journal of allergy and clinical immunology. 2006 Dec; 118(6); 1320-6. [PubMed: 17157663 ].
Slifka, 2004: Slifka MK. Immunological memory to viral infection. Current opinion in immunology. 2004 Aug; 16(4); 443-50. [PubMed: 15245737].
Weltzin et al., 2003: Weltzin R, Liu J, Pugachev KV, Myers GA, Coughlin B, Blum PS, Nichols R, Johnson C, Cruz J, Kennedy JS, Ennis FA, Monath TP. Clonal vaccinia virus grown in cell culture as a new smallpox vaccine. Nature medicine. 2003 Sep; 9(9); 1125-30. [PubMed: 12925845 ].