Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.
Page K, Melia MT, Veenhuis RT, et al.;
N Engl J Med. 2021 Feb 11;384(6):541-549. [Full text]
Summary by Leanna Rucker
Hepatitis C virus (HCV) is a single-stranded, enveloped RNA virus that accounts for nearly 15-20% of acute hepatitis cases. After initial infection with HCV around 30% of individuals will spontaneously clear the virus, while the majority develop chronic HCV infection. In those with chronic HCV infection, 15 -30%will subsequently develop cirrhosis which has its associated complications. Despite high cure rates with effective antiviral agents, it is estimated that 71 million people live with chronic HCV infection globally, with rapidly increasing incidence within the United States.
HCV is transmitted primarily through parenteral exposures of infectious blood or bodily fluids that contain blood. Those at risk for HCV infection include people with HIV, current or former use of injection drugs, prior recipients of transfusions and organ transplants (specifically before July 1992), hemodialysis patients, healthcare works, and children born to mothers with HCV. In the United States, injection-drug use is currently the most common mode of HCV transmission. A safe and effective vaccine aimed at preventing chronic HCV infection is an area of clinic interest. The World Health Organization has developed a goal to eliminate viral hepatitis as public health problem and reduce new infections by 90% by 2030.
Patient population and Design
This study design was a multi-center, phase 1-2 clinical trial assessing the safety and efficacy of a two-dose vaccine series for the prevention of chronic HCV infection. The trial took place between 2012 and 2018 at Johns Hopkins University, the University of California, San Francisco, and the University of New Mexico.
The patient population was comprised of 548 healthy, HCV-uninfected adults ages 18 to 45, with recent use of injection drugs within the past 90 days. Of those enrolled, participants were randomly assigned in a 1:1 ratio to receive intramuscular injections of a vaccine or saline placebo. The vaccine regimen was comprised of vaccines derived from chimpanzee adenovirus 3 (ChAd3) and modified vaccinia Ankara (MVA), administered on days 0 and 56 respectively. These vectors encoded the nonstructural proteins of HCV genotype 1b, one of the most common genotypes in the United States. Of note, randomization was stratified according to sex and IFNL3 genotype as these factors affect the likelihood of progression to chronic HCV infection.
The study was double-blinded as both participants and the trial investigators were unaware of randomization assignments and results throughout the trial. Participants were followed monthly for HCV infection for a total of 20 months after enrollment. Those with confirmed HCV infection were followed 9 months after detection.
The study assessed primary and secondary outcomes, in addition to vaccine safety and immunogenicity. The primary outcome, or primary efficacy end point, was prevention of chronic HCV infection, defined by persistent viremia for 6 months. This diagnosis was established by confirming that the same virus was present in the initial blood sample in which HCV RNA was detected, as well as at month 6 from incident infection, and a third sample collected between the two visits. Secondary outcomes, or exploratory efficacy analyses, included assessment of potential vaccine effects on incidence of primary HCV infection, incidence of chronic HCV infection for 9 months, the geometric mean peak HCV RNA level after infection, and incidence of chronic infection with genotype 1.
Safety was evaluated by the incidence of vaccine-related serious adverse events occurring during the trial period. Participants were asked to keep daily records of their body temperature and monitor for presence of post injection adverse events for 8 days following vaccine or placebo administration. Laboratory abnormalities were monitored with monthly complete blood counts, alanine aminotransferase (ALT) levels, and creatinine.
Vaccine immunogenicity was measured with serial ELISpot assays performed at baseline and after vaccine administration. Participants were deemed as having a response to the vaccine or placebo if they had tested negative for HCV-immune responses at baseline, and had a positive immune response to at least one peptide pool after injection.
Of the 548 enrolled participants, a total of 455 participants received both injections of vaccine or placebo. 75 participants became infected with HCV during study follow-up, with 37 (13%) participants in the vaccine group and 38 (14%) in the placebo group. A total of 36 met criteria for chronic HCV infection after 6 months, with approximately equal representation between groups.
Regarding the primary outcome, investigators found no evidence of prevention of chronic HCV infection among the vaccine or placebo group, HR primary per-protocol of 1.53 [95% CI 0.66 to 3.55]. Data was also analyzed using a modified intention-to-treat analysis, with similar findings. Based on these results, it was concluded that there was no evidence of vaccine efficacy.
Secondary outcomes were analyzed in a similar manner and found no evidence of a vaccine effect on the incidence of primary HCV infection, incidence of chronic HCV infection at 9 months, or incidence of chronic HCV infection with genotype 1. In contrast, the geometric mean peak HCV RNA level was found to be lower in the vaccine group compared to placebo 152.51×103 IU per milliliter [95% CI, 33.5×103 to 686×103] vs 1804.93×103 IU per milliliter [95% CI, 565×103 to 5764×103].
Regarding safety, no vaccine-related serious adverse events were reported. The most frequent laboratory abnormality was ALT elevation, which was associated with substance use and HCV infection.
Finally, immunogenicity data was assessed before HCV infection and was available for 145 vaccine recipients and 149 placebo recipients. T-cell responses to HCV were detected in 78% participants who received vaccine versus only 3% of placebo recipients.
While the vaccine regimen did demonstrate immunogenicity measured by HCV-specific T-cell responses, lower peak HCV RNA levels in HCV-infected individuals, and an acceptable safety profile, there was a lack of vaccine efficacy in preventing chronic HCV infection.
The study targeted self-reported injection drug users, a population critical to the prevention of chronic HCV infection. But there were difficulties retaining participants, ensuring adherence with the study protocol, and maintaining regularly scheduled follow-up. The authors cite the use of resources and expertise to engage this particular patient population, suggesting that further vaccine research within this population is feasible. Though the majority of participants were White males, there was representation of various racial and ethnic groups, including multiracial, Black, American Indian, and Asian groups. This was likely related to recruitment within the areas surrounding the academic institutions involved in the study. For providers practicing in diverse, metropolitan settings where injection drug use is prevalent, this study population is representative.
While the vaccine regimen was not associated with lower incidence of chronic HCV infection compared to placebo, perhaps there still may be clinical significance in the positive study findings of vaccine immunogenicity and lower HCV RNA levels. Further investigation is required to learn if these attributes influence HCV transmission or progression to chronic liver disease. This study highlighted that continued research on vaccine development for HCV infection prevention is needed, particularly in this high-risk population.
|F: Follow up
|Monthly for 20 mo
|Yes, stratified according to sex and IFNL3 genotype
|I: Intention to treat
|No, modified intention-to-treat and per-protocol
|S: Similar at baseline
|E: Equal treatment
|S: Source (funding)
|National Institute of Allergy and Infectious Diseases