The new ACAM2000™ vaccine and other therapies to control orthopoxvirus outbreaks and bioterror attacks

The 2003 monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog is susceptible to MPXV infection and that the ensuing rash illness is similar to human systemic orthopoxvirus (OPXV) infection, including a 7-to 9-day incubation period and, likely, in some cases a respiratory route of infection; these features distinguish this model from others. The need for safe and efficacious vaccines for OPVX in areas where it is endemic or epidemic is important to protect an increasingly OPXV-naïve population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. Although smallpox has been eradicated (5), orthopoxviruses (OPXVs), such as variola virus (VARV) (6, 32), monkeypox virus (MPXV) (3, 10, 57), vaccinia virus (VACV) (4, 76), and others (53,68,77), are a continuing public health concern (61, 67). Due to cellular and humoral protective effects (7,15,16,46,73), the traditional live VACV-based smallpox vaccines provide cross-protection against multiple OPXV threats (48). Unfortunately, the cessation of routine vaccination (37) has left much of the global population fully susceptible to OPXV infections (34), and the adverse effects of first-and secondgeneration vaccines (78) coupled with increases in the global immunocompromised population (59) underline the need for continued development and testing of safer smallpox vaccines (30).Testing of smallpox vaccines requires the development of relevant animal models. Current smallpox vaccine testing animal models include ectromelia virus (ECTV) infection of mice (75), VACV infection of mice (63), rabbitpox virus (RPXV) and VACV infection of rabbits (1, 18), VARV and MPXV infection of nonhuman primates (NHP) (13,19,21,25,26,31), and others (65, 74). Limitations of current models include abbreviated disease incubation periods and/or differences from human systemic orthopoxvirus disease presentation and progression The validation of alternative animal models for smallpox vaccine testing is an ongoing effort (2, 19, 39).The MPXV outbreak in the United States in 2003 (3) identified a potential alternative model as it established that MPXV can be transmitted to black-tailed prairie dogs (Cynomys ludovicianus) (42). Investigations of the MPXV outbreak and epidemiological, immunological, and pathological studies of prairie dogs infected with MPXV (8,12,27,28,35,38,43,57,58,64,69,74,80) determined that this rodent species can manifest MPXV infection similar to human systemic OPXV disease. This disease model shares a respiratory route of infection, similar disease incubation period, and similar rash illness (20,29,38,42,80) with human MPXV and VARV infections, thus making it a potentially useful small animal model for testing vaccines and therapeutics (29,70). A particular strength of this model is its 7-to 9-day incubation period, which is more similar to that seen in human disease than many other a...

Section: Discussionsupporting

confidence: 92%

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Keckler

Carroll

Gallardo-Romero

et al. 2011

“…In agreement with our previous studies, 10 6 T cells adoptively transferred into nude mice failed to protect them from infection or to reduce viral loads (29). In contrast, BCV treatment in combination with an adoptive transfer of 10 5 or 10 4 T cells conferred survival to 100% or 60% of mice, respectively.…”

Section: Discussionsupporting

confidence: 92%

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

Zaitseva

McCullough

Cruz

et al. 2015

Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10 5 PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ϳ10 to 20 days after treatment termination. Nude mice reconstituted with 10 5 T cells prior to challenge with 10 4 PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10 5 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCEMass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immunedeficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immunedeficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. Smallpox was eradicated following a global immunization program using live vaccinia virus (VACV) vaccine implemented by the World Health Organization (WHO). Routine smallpox vaccination was subsequently discontinued due to a low but significant risk of severe adverse reactions. A...

“…Of note, the specific cellular immune response triggered by nonreplicating poxvirus vectors is of the Th1 type, which may explain the weak antibody response elicited by these vectors (23,25). to be produced using highly attenuated smallpox vaccine strains such as, for instance, ACAM2000 (24).…”

Section: Discussionmentioning

confidence: 99%

Potent and Broadly Reactive HIV-2 Neutralizing Antibodies Elicited by a Vaccinia Virus Vector Prime-C2V3C3 Polypeptide Boost Immunization Strategy

Marcelino¹,

Borrego

Rocha

et al. 2010

Human immunodeficiency virus type 2 (HIV-2) infection affects about 1 to 2 million individuals, the majority living in West Africa, Europe, and India. As for HIV-1, new strategies for the prevention of HIV-2 infection are needed. Our aim was to produce new vaccine immunogens that elicit the production of broadly reactive HIV-2 neutralizing antibodies (NAbs). Native and truncated envelope proteins from the reference HIV-2ALI isolate were expressed in vaccinia virus or in bacteria. This source isolate was used due to its unique phenotype combining CD4 independence and CCR5 usage. NAbs were not elicited in BALB/c mice by single immunization with a truncated and fully glycosylated envelope gp125 (gp125t) or a recombinant polypeptide comprising the C2, V3, and C3 envelope regions (rpC2-C3). A strong and broad NAb response was, however, elicited in mice primed with gp125t expressed in vaccinia virus and boosted with rpC2-C3. Serum from these animals potently neutralized (median 50% neutralizing titer, 3,200) six of six highly divergent primary HIV-2 isolates. Coreceptor usage and the V3 sequence of NAb-sensitive isolates were similar to that of the vaccinating immunogen (HIV-2ALI). In contrast, NAbs were not reactive on three X4 isolates that displayed major changes in V3 loop sequence and structure. Collectively, our findings demonstrate that broadly reactive HIV-2 NAbs can be elicited by using a vaccinia virus vector-prime/rpC2-C3-boost immunization strategy and suggest a potential relationship between escape to neutralization and cell tropism.