Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV)

Abstract

In view of presumed non-pathogenicity, tumor suppressive properties, and site-specific integration of the viral genome the human parvovirus, adeno-associated virus (AAV) has gained great interest as a gene transduction vector. Data on the seroprevalence of antibodies to AAV vary between reports, probably due to the different serological methods used. In order to understand better the immune response to AAV during natural infection, sera from different age groups and various geographical regions were compared for AAV antibodies using an ELISA. The data show that the prevalence of antibodies to AAV is similar in Europe (Germany, France, and Switzerland), Brazil, and Japan, indicating worldwide infection. It was confirmed that infection takes place during childhood. However, declining seropositivity thereafter and a second increase of seropositivity after 30 years of age suggests reinfection or reactivation of latent virus in particular as the prevalence of IgM antibodies in adults is relatively high. Furthermore, pregnant women were found to be significantly more frequently seropositive than non-pregnant controls, hinting at a reactivation of persistent AAV (up to 80% of women carry AAV in genital tissue) in specific hormonal conditions, e.g., pregnancy. Cross-reaction of serum antibodies with the different AAV types (defined by complement fixation) was observed by ELISA and neutralization tests confirming earlier results. The results suggest an unstable AAV antibody response allowing lifelong reinfection or reactivation of persisting virus possibly due to partial immunotolerance after an infection in utero, at delivery or during early infancy.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

“…In approximately 20-60% of this subpopulation, an adaptive humoral response results in the development and maintenance of antibodies capable of neutralizing subsequent infection by AAV2 (neutralizing antibodies (NAbs)). [8][9][10][11][12][13][14][15][16][17][18][19] The existence of NAbs can limit rAAV therapeutic applications that rely on systemic vector administration, for example, by interfering with cell surface binding or promoting reticuloendothelial clearance and destruction of AAV vectors. [20][21][22] Additionally, previous human studies have observed that NAbs against AAV2 cross-neutralize other serotypes of AAV.…”

Immune responses to gene therapy vectors: influence on vector function and effector mechanisms

“…Infection by the nonpathogenic AAV2 is common, and the prevalence of anti-AAV2 antibodies ranges from 35 to 80% according to the age group and geographic location. 25,30,31 Several studies have shown that anti-AAV antibodies have neutralizing effects that decrease the efficiency of in vivo vector infection in the liver 32 or lungs, 31 and therefore limit the chances of success with repeated administration of these vectors. Other studies, in contrast, have established that this humoral response has no influence on the efficiency of infection with the vector administered within the muscle 33 or lungs.…”

“…Furthermore, serum anti-AAV IgMs have been found in humans after recent AAV infection or reactivation of a latent form of the virus. 30 Antibodies to AAV serotypes 1, 3, and 5 are common in humans, and their prevalences increase with age. However, their neutralizing effects seem less potent than those of anti-AAV2 antibodies.…”

AAV for pain: steps towards clinical translation

“…No apparent ill effects have ever been associated with AAV even though the majority of humans have been exposed to AAV, as judged by serum neutralizing antibodies against at least one serotype. [15][16][17][18] It is therefore a common notion, that any derivative product should be at least as harmless.…”