Capsule

Hepatitis C Vaccine Development

The biosafety community is routinely called on to inform and remind (at least annually) anyone handling human blood, human blood products, or other human specimens of the US Occupational Health and Safety Administration’s bloodborne pathogen (BBP) standard. In essence, the BBP standard says to handle all such materials as if infectious. The main BBPs of concern are hepatitis B virus (HepB), hepatitis C virus (HepC), and HIV-1. The BBP standard states that researchers are to be informed of a vaccine against HepB, which is to be made freely available to employees. If you have wondered why there is a safe and efficacious vaccine available against HepB but not against HepC, a recent mini-review by Pierce et al ¹ gives an overview of where HepC vaccine development currently stands. Unfortunately, and for similar reasons, developing a HepC vaccine may prove just as difficult as it has been to develop an efficacious HIV-1 vaccine, a process that has been a decades-long endeavor that is not yet realized. While combined data from chronically infected HepC carriers, vaccinated chimpanzees, and clinical trial vaccines suggest that cellular immunity (to nonstructural viral proteins) and humoral immunity (to the viral envelope) play a role in protection from HepC infection, this review concentrates on obstacles and approaches to generate broadly HepC-reactive neutralizing antibodies (nAbs).

HepC-infected individuals, whether in acute or chronic stages of infection, usually develop HepC-reactive antibodies. Most naturally occurring antibody responses are directed to immunodominant, nonneutralizing epitopes—termed immunogenic decoys—on the HepC envelope glycoproteins E1 and E2. Potential vaccine immunogens should avoid generating wasted antibodies to these epitopes. Of the few nAbs generated during natural infection, HepC has evolved means to thwart their antiviral activity. For example, glycosylation sites near neutralization epitopes on E2 form a type of glycan shield that limits access to neutralizing epitopes by nAbs. Moreover, like HIV-1, HepC is an RNA virus that relies on a virus-encoded, error-prone nucleic acid polymerase for viral replication. Selection pressure on mutations arising from this inexact RNA replication mechanism results in an individual soon harboring numerous HepC quasi-species following initial infection from a single virus particle—this has also contributed to the generation of drug-resistant HepC variants in some patients that have received otherwise highly effective (and costly) medical treatment targeting nonstructural viral proteins. Difficulties in HepC vaccine development are also caused by the same error-prone, mutation-generating RNA polymerase because selective pressure from neutralizing antibody activity generates neutralizing antibody-escape mutants within otherwise HepC-immune individuals.

Facing these obstacles, vaccine researchers, including the authors of this review, are approaching rational HepC vaccine design by identifying potential E1 and E2 epitopes that are functionally and antigenically conserved across HepC genotypes and subtypes. An example is work by the authors to use 3-dimensional structural analysis on those portions of E1 and E2 required for target cell recognition by HepC to identify functionally conserved epitopes. In theory, nAbs against these epitopes should be broadly reactive, and any mutations arising through nAb-mediated selective immune pressure that affect functionality should not survive. From a biosafety perspective, it is encouraging that in vitro testing of the nAb reactivity to these epitopes can be performed through nonpathogenic pseudotyped viruses instead of HepC itself.

Although the potential role of cellular immune responses in vaccine-induced protection from HepC infection is barely touched on, this review offers optimism that viable targets for vaccine-induced antibody responses will soon be identified for incorporation into an efficacious vaccine.