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Combination Hepatitis A and B Vaccine to Induce Immunity in Non-responders

2014-08-27 03:13:34 | BioPortfolio

Summary

Hepatitis B is a vaccine preventable infection which can be transmitted through occupational exposure. Approximately 15% of patients will not respond to an initial series of vaccination. Of those re-vaccinated approximately fifty percent will respond. On the basis of poor response to a third series, repeat vaccination is not recommended and non-responders are considered vulnerable to infection. Cardell studied the use of double dose combination hepatitis A and B vaccine (Twinrix) in non responders who had received four or more doses previously and found a high response rate suggesting this vaccine and dose could be effective. The investigators study seeks to duplicate the findings of Cardell, using a more strict definition of non-responder (6 or more previous doses).

Description

Hepatitis B is a blood borne infection that is highly transmissible through occupational exposure in healthcare. The maximal risk for transmission occurs with needle-stick injuries. However, the majority of cases of transmission probably occur with lower risk exposures. Overall, the risk of transmission of hepatitis B from an infected patient to a susceptible health care worker is estimated at 23-62% after a single parenteral exposure (US PHS 2001).

Acute hepatitis B is symptomatic in approximately 30% of cases, with 0.1-0.5% of these cases developing fulminant hepatitis with a risk of death. Another 5% of cases will go on to chronic hepatitis B infection with an associated risk of cirrhosis and hepatocellular carcinoma.

This transmission can be prevented by vaccination of health care workers prior to exposure. Successful vaccination can provide years of protection (Alavian 2008) Consequently, the US CDC and the Canadian National Advisory Committee on immunization recommends vaccination for all heath care workers who will have contact with blood, bodily fluids, or sharps. A test for immunity should be performed after completion of vaccination, because ~15% of healthy adults do not respond to a primary vaccine series.

For those health care workers who are not immune after a first series, a second immunization attempt should be made. The expected rate of response in this group is 30-50% (US PHS 2001).Those who fail to develop a protective antibody response (anti-hepatitis B surface antigen antibody titre of >=10mIU/ml), are labelled non-responders and should be considered susceptible to infection. A third attempt at vaccination is currently not recommended because the estimated rate of response is only 10%.

When susceptible, vaccine non-responding health care workers have an occupational exposure to hepatitis B, the CDC recommends treatment with two doses hepatitis B immune globulin, a blood product which has an undefined risk of transmitting yet unknown blood borne infections.

A recent study by Cardell (2008) looked at the vaccine response to three doses of double-dose Twinrix® in patients who had failed at least 4 doses of hepatitis B vaccine. The response rate in 44 health care workers who had failed 4 doses was 95%. This was much higher than the documented 30-50% response rate quoted by the CDC.

The important distinction between Cardell et al, and our study, is that our entry criteria are more stringent, and represent the point at which we do not know what to recommend to "non-responder" physicians and other healthcare workers. The current recommended standard is to provide two full series of vaccine before concluding that a person is a non-responder. Cardell and others (Wismans, 1988; Craven, 1986; Westmoreland, 1990), by including patients who had not responded to a single series of vaccination, but who had also not received a full second series, potentially over-estimate efficacy of their regimes, and thus they don't provide us with guidance as to what to do in the true non-responder subgroup. The importance of completing two full series of immunizations (6 total doses) was highlighted by Clemens (1997) who demonstrated that there was a significant increase in the proportion of responders with the last 2 doses of vaccine in the second series.

The Cochrane meta-analysis of hepatitis B vaccination of health care workers suggests that there is currently insufficient evidence insofar as the treatment of non-responders (Chen, 2005). Our study may provide that information if profoundly positive. More likely, it will serve as the support for a larger study that could provide meaningful guidance for the management of health care workers who have truly failed two full series of immunization attempts, and who currently would be labelled as susceptible. This population represents a significant minority of healthcare workers (~5%), who remain at risk for a life-threatening occupational disease despite vaccination.

Other mechanisms of immunization have been attempted in the non-responder group including booster doses (Das, 2003), intradermal administration (Yasumura, 1991), adjuvant interferon (Goldwater, 1994), newer formulations/designs of vaccine such as a triple-valent vaccine (Zuckerman, 2001; Rendi-Wagner, 2006), vaccine with adjuvant (Jacques, 2002), or particle based DNA vaccines (Rottinghaus, 2003). These have shown demonstrable effect, but all studies include subjects who have not responded to a single series of immunization, and, other than Cardell et al, none have resulted in response in the majority of non-responders. Our study utilizes a currently licensed vaccine, at doses demonstrated to be safe, with Cardell's evidence supporting the hypothesis that it may be highly effective.

The use of higher dose recombinant vaccine on its own did not show a demonstrable effect over further doses (Goldwater, Randomized, comparative trial of 20 micrograms vs 40 micrograms Engerix B vaccine in hepatitis B vaccine non-responders., 1997). However, there is some evidence that the combination A/B vaccine may produce more immunogenicity for both hepatitis A and B responses (Czeschinski, 2000).

Thus, our study will test a new strategy for vaccination in a group of selected at-risk healthcare workers for whom there is no other currently recommended vaccination strategy. The potential impact of the study is considerable.

Our study will expand on Cardell's by looking specifically at those who have failed two complete series of vaccinations (6 or more doses) who would be otherwise labelled as non-responders according to the CDC criteria. Our hypothesis is that the combined hepatitis A and B vaccine (Twinrix®) given at double-dose as in Cardell's study will induce protective immunity in these non-responders at a rate much higher than the traditionally quoted 10% response rate.

Study Design

Allocation: Non-Randomized, Control: Historical Control, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Conditions

Hepatitis B

Intervention

Twinrix

Location

Mount Sinai Hospital
Toronto
Ontario
Canada
M5G 1K5

Status

Recruiting

Source

Mount Sinai Hospital, Canada

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:13:34-0400

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Medical and Biotech [MESH] Definitions

INFLAMMATION of the LIVER in humans due to infection by VIRUSES. There are several significant types of human viral hepatitis with infection caused by enteric-transmission (HEPATITIS A; HEPATITIS E) or blood transfusion (HEPATITIS B; HEPATITIS C; and HEPATITIS D).

A family of hepatotropic DNA viruses which contains double-stranded DNA genomes and causes hepatitis in humans and animals. There are two genera: AVIHEPADNAVIRUS and ORTHOHEPADNAVIRUS. Hepadnaviruses include HEPATITIS B VIRUS, duck hepatitis B virus (HEPATITIS B VIRUS, DUCK), heron hepatitis B virus, ground squirrel hepatitis virus, and woodchuck hepatitis B virus (HEPATITIS B VIRUS, WOODCHUCK).

A species in the genus HEPATOVIRUS containing one serotype and two strains: HUMAN HEPATITIS A VIRUS and Simian hepatitis A virus causing hepatitis in humans (HEPATITIS A) and primates, respectively.

INFLAMMATION of the LIVER in humans caused by HEPATITIS DELTA VIRUS, a defective RNA virus that can only infect HEPATITIS B patients. For its viral coating, hepatitis delta virus requires the HEPATITIS B SURFACE ANTIGENS produced by these patients. Hepatitis D can occur either concomitantly with (coinfection) or subsequent to (superinfection) hepatitis B infection. Similar to hepatitis B, it is primarily transmitted by parenteral exposure, such as transfusion of contaminated blood or blood products, but can also be transmitted via sexual or intimate personal contact.

INFLAMMATION of the LIVER in humans caused by HEPATITIS C VIRUS, a single-stranded RNA virus. Its incubation period is 30-90 days. Hepatitis C is transmitted primarily by contaminated blood parenterally, and is often associated with transfusion and intravenous drug abuse. However, in a significant number of cases, the source of hepatitis C infection is unknown.

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