Thursday, 18 April, 2024
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New vaccines offer hope for Hepatitis B treatment in SA

Vaccination is key to eliminating hepatitis B virus (HBV) infection in South Africa, where despite the introduction of immunisation in 1995, infection remains endemic and vaccine coverage is incomplete.

In the SA Medical Journal, G U van Zyl, T Maponga, H Rabie and J Taljaard, all from Stellenbosch University, write that apart from infants, non-immune adults at risk of infection through their occupation or with behavioural risk factors should also receive vaccination.

There are thousands of South Africans with diabetes mellitus (a prevalence of almost 13%), obesity, HIV (8.45m) or older age (5m >60 years old), associated with a poorer vaccine response.

Recently two new hepatitis B vaccines have been licensed: HEPLISAV-B includes an adjuvant that improves immunogenicity and has shown improved vaccine response in people with HIV, old age or diabetes mellitus, and PreHevbrio, which includes three hepatitis B surface protein domains, instead of one, which may also be more immunogenic, although clinical study data are still limited.

These two novel vaccines have not yet been investigated in children and licensed in SA. If HEPLISAV-B becomes available, it may be particularly valuable to target high-risk groups, like people with HIV, who show a poor response to the currently licensed vaccine.

Background

There are ~8m people with HIV in this country, and of around 260 000 pregnancies in 2022, 8 000 children became infected, despite a prevention of mother-to-child transmission (PMTC) programme.

SA also still has endemic HBV infection, with an estimated 3% of the population having chronic HBV infection.

However, there is an absence of nationally representative seroprevalence studies to confirm HBV seroprevalence, or the rate of co-infection of HBV and HIV.

A Western Cape study based on 2008 antenatal samples found a similar prevalence of ~3% in pregnant women with or without HIV, while another study using seroincidence samples from 2009 from KwaZulu-Natal showed a HBV surface (S) antigen (HBsAg) prevalence of 16/215 (7.4%) among individuals with HIV, compared with 14/29 (4.8%) among those without: this was not statistically significant, but six of the 16 with HIV had hepatitis B e-antigen (HBeAg), and none without HIV (p=0.0185).

Since HBeAg is a marker of infectivity, this suggests a much higher transmission risk of HBV when infants are born to mothers with HIV.

Progress towards elimination

Vaccination is the most important intervention to prevent HBV infections and protect people at high risk of infection.

Initially referred to as the Australia antigen, HBV was shown to be the cause of hepatitis in 1966. The characterisation of the virus and its surface antigen resulted in the production and licensing of vaccines.

The first was a purified and inactivated HBsAg product from the plasma of patients with chronic hepatitis B infection. This was followed by the production of a recombinant HBsAg vaccine in yeast cells.

Although HBV vaccines have been available internationally since 1982, they were only introduced in the SA expanded programme of immunisation (EPI) in 1995.

Universal HBV vaccination, as part of the EPI, given to children at six, 10 and 14 weeks of age and at 18 months since 1995, has resulted in a significantly lower prevalence of chronic hepatitis B in subsequent birth cohorts: from 8/622 (1.29%) born before 1995 to 0/572 (0%) in a study of pregnant women from the Western Cape, and from 7.4% to <4.1% in birth cohorts born before or after 1995, in a large laboratory-based study of >100 000 samples from Gauteng.

A national measles rash surveillance study showed that only 0.4% of residual samples from children from the post-1995 birth cohort had evidence of current HBV.

In an investigation of low-risk blood donors, the prevalence of HBV was 0.84% in samples in individuals born before 1995, decreasing to 0.14% in individuals born after 1995.

Gaps

But vaccination has unfortunately not eliminated HBV, and the prevalence is higher in people with Aids and male sex. Individuals who have not been vaccinated, due to being born before 1995, or who did not access vaccination, or who were perinatally exposed before being vaccinated, may be at risk of chronic hepatitis.

Despite several years of routine infant vaccination starting in 1995, local studies indicate that HBV is far from eliminated in the post-vaccine cohort, with incomplete vaccine coverage (estimated to be only 71% for three doses as part of EPI in 2015). Despite study heterogeneity, there is an overall higher prevalence in people with Aids: 1.7% of children with HIV from Gauteng compared with none in HIV-negative children from a vaccinated birth cohort, and 13% of children with HIV, compared with 7.5% from KwaZulu-Natal infants, being HBV DNA positive in 2011.

Apart from childhood EPI vaccination, the SA National Guidelines for the management of viral hepatitis advise that the following at-risk individuals should also be vaccinated: healthcare workers, residents and workers of facilities for the mentally disabled, emergency service workers, household contacts of HBsAg-positive persons, men who have sex with men, sex partners of HBV-infected individuals, intravenous drug users, persons with end-stage kidney disease, patients who require organ transplants or have chronic liver disease and those with HIV infection.

Yet despite these guidelines, there is no adult HBV vaccination programme. Vaccination of high-risk individuals is also inadequate, as a study at an academic centre showed fewer than half of healthcare workers had been vaccinated.

Testing of key populations, such as pregnant women, is also not incorporated into programmes. Identifying mothers with hepatitis B is key to preventing mother-to-child transmission.

Moreover, despite guidelines advising this, and the option of using rapid tests, there is currently no national strategy to test pregnant women for HBsAg.

Based on the estimated number of patients with HIV and the hepatitis B prevalence in HIV-infected patients, one could assume that at least 300 000 cases would be co-infected. As HBV may reactivate in patients with HIV, these individuals may be a source of ongoing horizontal or mother-to-child hepatitis B transmission when not on treatment.

Moreover, people with Aids who disengage from care would not have the benefits of treatment

The potential role of vaccines

Several new immunogenic vaccines have been internationally licensed. One is a yeast recombinant S-antigen vaccine with a cytosine-phosphate-guanosine oligodeoxynucleotide (CpG) adjuvant, which has been licensed in the USA and Europe but not yet approved by the SA Health Products Regulatory Authority (SAHPRA).

This vaccine has been shown to be effective in vaccine non-responders and immune-suppressed individuals. Additionally, it induces a high level of protection in immune-competent individuals after a course of just two vaccine doses, whereas four doses provide a high proportion of seroprotection in haemodialysis patients.

When three vaccine doses were given, it resulted in seroprotection of all 68 previously unvaccinated patients with Aids.

This CpG adjuvant vaccine, marketed as HEPLISAV-B, may increase the seroprotection rates in SA HIV-infected patients, if it becomes available

Other priority groups for a more immunogenic vaccine may be those with diabetes mellitus, due to its high burden in SA, and their lower vaccine response rates. However, data on the safety and efficacy of this vaccine in children are still lacking.

The novel three-antigen vaccine (pre-S1 and pre-S2 and S-antigens expressed in mammalian cells to assure native glycosylation), marketed as PreHevbrio, has also been licensed in the USA, and as PreHevbri in the European Union. It appears potentially more immunogenic in individuals ≥45 years old, and may therefore have value in vaccine non-responders, as it provides additional B-cell epitopes.

But data on its value in other patients with a high risk of vaccine non-response, including HIV-infected individuals, are lacking, and it has also not been investigated in children.

While these novel vaccines are unavailable, alternative strategies for the management of vaccine non-responders, including higher vaccine dose or intradermal injection, must be explored. Should HEPLISAV-B or PreHevrio become available in SA, their role will depend on the following: is it safe and efficacious in children?

Is it affordable to the public sector, and in the case of HEPLISAV-B, can a two-dose HEPLISAV-B vaccine schedule administered to infants or immune-competent individuals replace the current three-dose vaccine schedule?

Would HEPLISAV-B be safe and effective when the first dose is given at birth to prevent perinatal transmission? Could the new vaccines be included in co-formulated preparations with other childhood vaccines?

Clinical trials in different SA patient groups and implementation research are needed to establish whether there is a role for these novel vaccines in reducing hepatitis B prevalence, and ultimately in eliminating hepatitis B infection in this country.

And if the vaccines are introduced, this should also be accompanied by public awareness campaigns on their safety and benefits to limit the spread of disinformation.

 

SA Medical Journal article – The role of new hepatitis B vaccines in South Africa (Creative Commons Licence)

 

See more from MedicalBrief archives:

 

Millions of unnecessary deaths from hepatitis globally

 

Experts call for hepatitis B birth-dose vaccine

 

SA children should be vaccinated against Hepatitis B at birth

 

 

 

 

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