Elsevier

Vaccine

Volume 31, Issue 48, 19 November 2013, Pages 5772-5777
Vaccine

The live attenuated chimeric vaccine rWN/DEN4Δ30 is well-tolerated and immunogenic in healthy flavivirus-naïve adult volunteers

https://doi.org/10.1016/j.vaccine.2013.07.064Get rights and content

Highlights

  • We evaluated two lots of a novel chimeric live attenuated WNV candidate vaccine in two Phase I clinical trials.

  • The first trial evaluated 103 or 104 PFU of vaccine given as a single subcutaneous dose.

  • The second trial evaluated a new lot of the vaccine given at a dose of 105 PFU with a booster dose given 6 months later.

  • A single subcutaneous dose induced seroconversion to wild-type WNV NY99 in 55%–75% of vaccinees.

Abstract

WNV has become the leading vector-borne cause of meningoencephalitis in the United States. Although the majority of WNV infections result in asymptomatic illness, approximately 20% of infections result in West Nile fever and 1% in West Nile neuroinvasive disease (WNND), which causes encephalitis, meningitis, or flaccid paralysis. The elderly are at particular risk for WNND, with more than half the cases occurring in persons older than sixty years of age. There is no licensed treatment for WNND, nor is there any licensed vaccine for humans for the prevention of WNV infection. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a recombinant live attenuated WNV vaccine based on chimerization of the wild-type WNV NY99 genome with that of the live attenuated DENV-4 candidate vaccine rDEN4Δ30. The genes encoding the prM and envelope proteins of DENV-4 were replaced with those of WNV NY99 and the resultant virus was designated rWN/DEN4Δ30. The vaccine was evaluated in healthy flavivirus-naïve adult volunteers age 18–50 years in two separate studies, both of which are reported here. The first study evaluated 103 or 104 PFU of the vaccine given as a single dose; the second study evaluated 105 PFU of the vaccine given as two doses 6 months apart. The vaccine was well-tolerated and immunogenic at all three doses, inducing seroconversion to WNV NY99 in 74% (103 PFU), 75% (104 PFU), and 55% (105 PFU) of subjects after a single dose. A second 105 PFU dose of rWN/DEN4Δ30 given 6 months after the first dose increased the seroconversion rate 89%. Based on the encouraging results from these studies, further evaluation of the candidate vaccine in adults older than 50 years of age is planned.

Introduction

West Nile virus (WNV) is a member of the Japanese encephalitis virus serogroup of the genus Flavivirus belonging to the Flaviviridae family [1]. Humans are thought to be only incidental hosts in the transmission cycle of WNV in which birds serve as the amplifying hosts of the virus and Culex mosquitoes serve as the primary vector [1]. Although the majority of cases of WNV are asymptomatic, approximately 20% of infections result in symptomatic West Nile fever or neuroinvasive disease (WNND) manifesting as encephalitis, meningitis, or flaccid paralysis resembling poliomyelitis [2], [3], [4]. The first outbreak of WNV in the Western Hemisphere occurred in New York in 1999, and since that time, WNV has become the leading vector-borne cause of viral encephalitis in the United States [1], [5]. By 2010, the number of adults infected with WNV in the U.S. was estimated to be nearly 3 million, with approximately 13,000 cases of WNND, almost half of which occurred in persons more than 60 years of age [6]. Importantly, the second largest recorded outbreak of WND in the United States occurred in 2012 with the CDC reporting 5674 cases, including 2873 (50.6%) of which were severe neurologic WNND and 286 deaths [7].

Economic analyses of WNV epidemics have demonstrated them to be costly [8], [9] and there is currently no licensed treatment or human vaccine for WNV. A low cost, efficacious vaccine may provide a cost-effective alternative for the prevention of WNV disease. Based on the success of the yellow fever and Japanese encephalitis vaccines, scientists at the Laboratory of Infectious Diseases have developed numerous live attenuated candidate flavivirus vaccines [10], [11], [12], [13], [14], [15]. Many of these were evaluated in clinical trial and were demonstrated to be attenuated and immunogenic in adult flavivirus-naïve subjects [16], [17], [18], [19], [20]. A similar strategy was employed to develop a recombinant live attenuated chimeric WNV vaccine designated rWN/DEN4Δ30. The vaccine was highly attenuated for neurovirulence and neuroinvasiveness in mice compared with its wild-type parent virus WNV NY99 [21], [22]. Importantly, non-human primates immunized with a single dose of rWN/DEN4Δ30 were completely protected against challenge with wild-type WNV NY99 [21]. rWN/DEN4Δ30 also demonstrated reduced ability to infect, replicate, and disseminate in both Culex and Aedes mosquitoes, diminishing its risk of transmission from vaccinees to other hosts [23]. These data encouraged further evaluation of the rWN/DEN4Δ30 vaccine in healthy flavivirus-naïve adult subjects. Here we describe two Phase I clinical trials of rWN/DEN4Δ30 designed to examine the safety, immunogenicity, and dosing regimen of this promising candidate vaccine.

Section snippets

Materials and methods

Two studies of the live attenuated chimeric vaccine rWN/DEN4Δ30 were conducted under an investigational new drug application (BB-IND #11940) reviewed by the US Food and Drug Administration. The studies were conducted at the Center for Immunization Research (CIR) at the Johns Hopkins Bloomberg School of Public Health and the Vanderbilt University School of Medicine and were approved by the Institutional Review Boards and Biosafety Committees of both institutions. The National Institute of

Study population

Healthy adult male and non-pregnant female subjects were recruited from the Baltimore, MD and Nashville, TN metropolitan areas. Informed consent was obtained from each subject in accordance with the Code of Federal Regulations (21 CFR 50). Healthy subjects between the ages of 18 and 50 years were enrolled if they met the following eligibility criteria: normal findings during physical examination; negative for antibodies to DENV-1, DENV-2, DENV-3, DENV-4, yellow fever, WNV, and St. Louis

Demographics

A total of 212 subjects were recruited and 82 subjects were enrolled in the two studies (Fig. 1). In total, 60 subjects received vaccine while 22 received placebo. Vaccinees ranged in age from 19 to 50 years while subjects receiving placebo ranged in age from 20 to 49 years. There was no statistically significant difference in mean age between subjects who received vaccine (31.3 years) and those who received placebo (31.6 years) (Table 2). There was also no statistically significant difference

Discussion

This vaccine candidate is a live chimeric flavivirus comprised of the prM and E protein genes of WNV NY99 and the capsid and non-structural protein genes of the attenuated DENV rDEN4Δ30. The vaccine is attenuated by two mechanisms: chimerization of WNV with a non-neuroinvasive flavivirus, DENV-4, and a 30-nucleotide deletion in the 3′ UTR. Chimerization is a potent attenuation strategy and was the major factor that led to the satisfactory balance between attenuation and immunogenicity of

Acknowledgments

These studies were supported by the National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health (No. NO1-AI-15444), through a contract with the Johns Hopkins Bloomberg School of Public Health and a subcontract with Vanderbilt University Medical Center.

References (32)

  • D.J. Gubler et al.

    Flaviviruses

  • E.B. Hayes et al.

    West Nile virus: epidemiology and clinical features of an emerging epidemic in the United States

    Annu Rev Med

    (2006)
  • J.J. Sejvar et al.

    Neurologic manifestations and outcome of West Nile virus infection

    JAMA

    (2003)
  • J.J. Sejvar et al.

    Acute flaccid paralysis and West Nile virus infection

    Emerg Infect Dis

    (2003)
  • N.P. Lindsey et al.

    West Nile virus neuroinvasive disease incidence in the United States, 2002–2006

    Vector Borne Zoonotic Dis

    (2008)
  • L.R. Petersen et al.

    Estimated cumulative incidence of West Nile virus infection in US adults, 1999–2010

    Epidemiol Infect

    (2013)
  • Cited by (45)

    • Recent expansion of mosquito-borne pathogens into Texas

      2019, Mosquitoes, Communities, and Public Health in Texas
    • An observer blinded, randomized, placebo-controlled, phase I dose escalation trial to evaluate the safety and immunogenicity of an inactivated West Nile virus Vaccine, HydroVax-001, in healthy adults

      2019, Vaccine
      Citation Excerpt :

      However, since the introduction of WNV into the United States in 1999, significant research efforts have been expended to create a viable vaccine for disease prevention in humans [9]. These efforts include live, attenuated chimeric vaccines [10–16], DNA vectored vaccines [10–19], recombinant subunit vaccines [20], and a variety of protein vaccines including chemically inactivated whole virus [21–23] and virus-like particles [24]. As an alternative to traditional formaldehyde-based vaccines, a novel hydrogen peroxide (H2O2) inactivation approach has been developed to produce a first-generation whole-virus vaccine against WNV that was tested at concentrations ranging from 1 to 40 mcg/dose [25–27].

    • Recent advances in human flavivirus vaccines

      2017, Current Opinion in Virology
      Citation Excerpt :

      The chimerisation of WNV with a non-neuroinvasive flavivirus and a 30 nucleotide deletion in the 3′UTR, highly attenuated the virus but still induced a strong immunogenic response in mice, geese and rhesus macaques [36,37]. This vaccine candidate was tested in two phase I clinical trials inducing a seroconversion rate against WNV above 80% in volunteers [38]. A research team at the Oregon Health & Science University created an inactivated WNV vaccine (HydroVax-001) using a novel, hydrogen peroxide-based process [39•].

    • Dengue Vaccines

      2017, Plotkin's Vaccines
    View all citing articles on Scopus
    1

    Current address is the Department of Pediatrics, Dartmouth University, Hanover, New Hampshire.

    View full text