Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers
Introduction
Cytomegalovirus (CMV) is a β-herpesvirus that causes a chronic, life-long infection that can result in significant morbidity and mortality. In healthy individuals, initial acquisition of CMV can cause a mononucleosis-like disease or more commonly an asymptomatic or unrecognized infection. In immunocompromised patients, especially those with advanced AIDS or solid organ and hematopoetic cell transplants, reactivation of CMV is a common cause of serious illness that can be fatal, and recently published data have suggested a possible role of CMV in atherosclerosis [1], immunosenescence [2] and autoimmune disease [3]. CMV is also the most common congenital infection (0.5–2% of newborn) and may produce severe, mild, or no disease at birth. Congenital CMV may also be a progressive disease that only manifests itself later in life [4], [5]. Development of a CMV vaccine to prevent congenital CMV disease is considered a public health priority [6].
Protective immunity to CMV involves both humoral and cellular immune mechanisms. Passive transfer of serum containing high titers of antibody to CMV reduces the risk of CMV disease in solid organ transplant recipients [7], [8], and adoptive transfer of cytotoxic T lymphocyte (CTL) clones specific for CMV antigens reconstitutes cellular immunity and prevents CMV viremia and CMV disease in bone marrow transplant recipients [9]. A role for antibody in protection from congenital disease has also been shown [10], and the risk of symptomatic CMV disease at birth and of neurological sequelae developing over the ensuing years is lower in infants born to mothers with pre-existing immunity [11]. Serum from CMV seropositive individuals has virus neutralizing activity in vitro, the principal target of which is the major CMV surface glycoprotein, gB [12], [13]. CMV seropositive individuals also have a high frequency of CMV-specific CD8+ CTL responses, the principal targets of which are a phosphoprotein with Mr 65 kDa (pp65) and an immediate-early protein with Mr 72 kDa (IE1) [14], [15].
Alphavirus replicon vector systems are being used as platforms for the development of prophylactic and therapeutic vaccines for infectious diseases and cancer [16], [17], [18], [19], [20], [21], [22]. The use of virus-like replicon particles (VRP) based on an attenuated strain of Venezuelan equine encephalitis virus is especially attractive because VRP are propagation-defective, single-cycle vectors that express heterologous proteins to high levels, target expression to dendritic cells, and elicit both humoral and cellular immune responses to the vectored gene products that have conferred protection against challenge in many animal disease models [23]. This system was utilized to produce AVX601, a two component VRP vaccine expressing human CMV pp65, IE1 and gB proteins [24]. Mice immunized with AVX601 develop high titers of anti-CMV antibodies as measured by a virus neutralization assay and robust T cell responses as measured by ex vivo, direct IFN-γ ELISPOT assay [25]. Described below are results from a randomized, double-blind, placebo-controlled Phase 1 safety and immunogenicity trial of AVX601 in healthy, CMV seronegative adult volunteers.
Section snippets
Vaccine
AVX601 is a two component alphavirus replicon vaccine expressing CMV proteins gB, pp65 and IE1. The separately formulated VRP components that comprise AVX601 express a soluble form of CMV gB (Towne strain) and a pp65/IEI fusion protein [25]. The vaccine design was based on observations that in vitro expression of pp65 and IE1 in VRP-infected cells was similar in single- and double-promoter replicons when these two proteins were expressed together, but expression of pp65 and IE1 was reduced when
Characteristics of the study population
Between March and June 2007, 123 subjects were screened and 40 eligible subjects were enrolled in the trial (Fig. 2). All subjects received their allocated treatment and were analyzed for safety, but two received only the first dose of study agent and did not complete the study; one subject in the IM placebo group prematurely discontinued after the Week 4 visit due to an adverse event (chest tightness within 15 min after placebo injections at Week 0) and one subject in the IM LD vaccine group
Discussion
The development of a CMV vaccine is a major priority. In fact, when the Institute of Medicine reviewed the priorities for vaccine development, a vaccine to prevent CMV was given the highest priority based on economic cost savings [6]. Although the first clinical trials of a CMV vaccine were conducted over 30 years ago, a vaccine for the prevention of CMV infection is not yet available. Approaches to CMV vaccines have included live attenuated vaccines, subunit and killed vaccines, DNA vaccines,
Acknowledgments
This study was funded by AlphaVax, Inc., and was presented in part at the IDSA/ICAAC Joint Meeting, Washington, DC, 25–28 October 2008.
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Current affiliation: Applied Genetic Technologies Corporation, Alachua, FL 32615, USA.