The prevalence of anti-Adeno associated virus neutralizing antibodies in South African people with Haemophilia B

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2021

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Ncete, Nolukholo

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Abstract

Adeno-associated virus (AAV) is the most common vector used in gene therapy for haemophilia Band one of the limitations of using this virus is the presence of pre-existing neutralising antibodies (NAbs )in individuals exposed to the virus in the general population. To date, there is a paucity of studies in the literature that have measured the prevalence of these NAbs in haemophilia B patients. The prevalence of anti-AAV NAbs among people with haemophilia varies with geographical location; consequently, extrapolation of prevalence data across regions is not possible. Knowledge of such prevalence is critical in the selection of participants for haemophilia B gene therapy intervention. The prevalence of anti-AAV NAbs in the South African haemophilia B population is currently unknown. This study had several objectives which were 1.) To measure the prevalence of anti-AAV NAbs of the different serotypes, including AAV1, AAV 2, AAV 5, AAV 6 and AAV 8 in South African people with haemophilia B, 2.) To identify the most prevalent serotype, the level of titres, possible cross-reactivity and compare these findings to what is known in the literature and 3.) To determine the possible risk factors associated with the development of anti-AAV neutralising antibodies. Serum samples were collected from 44 males with haemophilia B attending the Haemophilia Comprehensive Care Centre (HCCC) at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Controls comprise of 44 healthy non-haemophilia B volunteers. Each haemophilia B participant and control sample were tested for NAbs against five different serotypes of AAV, which included AAV1, AAV2, AAV5, AAV6 and AAV8 using a luciferase-based transduction inhibition assay. A positive result was defined as a titre of more than1 in 8 and the highest titre above 1 in 1030. AAV2 had the highest seroprevalence of NAbs in participants with haemophilia B at 95%,and39%of the participants had titres above 1030. This was followed by AAV6 with a prevalence of 82% with only 9% of participants having titres above 1030. AAV1 had a prevalence of 77%, and 20% had titres above 1030, making it the second most prevalent serotype with titres above 1030 after AAV2. AAV5 had a prevalence of 66% and had the lowest percentage of participants in the highest titre range (>1 in 1030) at 5%. The lowest seroprevalence of NAbs was seen with AAV8 (64%), and 32% of participants in this group had low titres ≥8-51.The frequency of all serotypes was higher in participants above 18 years of age and in those with severe haemophilia B disease. There was also a high AAV serotype co-prevalence observed at 59%, with AAV2 NAbs present in all participants that tested positive for any serotype. The seroprevalence in control participants followed a similar trend with frequencies of 75%, 100%, 61%, 80% and 64% in AAV1, AAV2, AAV5, AAV6 and AAV8, respectively. Anti-AAV2 neutralising antibodies are the most prevalent in the South African haemophilia B population. The AAV 5 and AAV8 vectors should be considered for use in gene therapy for our haemophilia B participants, as these two AAV serotypes had a lower prevalence with participants having lower titres.

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A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in Haematology, 2021

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