Depletion of measles virus glycoprotein-specific antibodies from human sera reveals genotype-specific neutralizing antibodies

Abstract

Measles virus (MV)-neutralizing antibodies in sera from vaccinated subjects are mainly directed against the haemagglutinin (H) protein. It has been shown previously that depletion of vaccinationinduced H-specific antibodies by co-culture of sera with cells expressing the MV Edmonston strain H glycoprotein resulted in almost complete elimination of neutralizing activity. In the present study, MV H and/or fusion (F) protein-specific antibodies were depleted from sera of naturally immune subjects. Early convalescent samples were collected 1.5 years after a well-characterized measles outbreak in Luxembourg caused by a genotype C2 virus, whilst late convalescent samples were collected from healthy Dutch subjects born between 1960 and 1970. Depletion of both H-and F-specific antibodies completely eliminated virus-neutralizing (VN) activity against MV Edmonston. However, in the early convalescent samples, residual VN antibody against wild-type MV genotype C2 was detected. This demonstrated that, although the majority of MVspecific VN antibodies recognized epitopes conserved between different genotypes, genotypespecific VN epitopes were also induced. In sera depleted of H-specific antibodies only, VN activity against MV Edmonston was not completely eliminated, demonstrating the presence of F-specific VN antibodies. In conclusion, this study demonstrated that a fraction of VN antibodies induced by wild-type MV genotype C2 does not neutralize MV strain Edmonston. In addition, it was shown that, in sera from naturally immune donors, the majority of VN antibodies are specific for MV H protein, but up to 10 % of neutralizing antibodies are specific for MV F protein. INTRODUCTIONMeasles remains an important cause of childhood morbidity and mortality in developing countries (WHO, 2008). The causative agent, measles virus (MV), is a member of the genus Morbillivirus, family Paramyxoviridae (Griffin, 2007). The virus is transmitted via the respiratory route and predominantly infects CD150-positive lymphocytes and dendritic cells (de Swart et al., 2007). MV infection is associated with immunosuppression, but paradoxically also results in life-long protection. Virus-neutralizing (VN) serum antibodies are the most important correlate of protection. VN antibody levels of 0.1-0.2 international units (IU) ml 21, equivalent to titres of approximately 1 : 8 to 1 : 16, have been shown to protect from disease (Chen et al., 1990; Samb et al., 1995). VN antibodies are directed exclusively to the MV transmembrane glycoproteins, the haemagglutinin (H) and fusion (F) proteins, and mostly recognize conformational epitopes (Bouche et al., 2002).We have demonstrated previously that, in sera collected from vaccinated subjects, MV-neutralizing antibodies are directed mainly to the H protein (de Swart et al., 2005). To this end, we used the stably transfected human melanoma cell line Mel-JuSo expressing the H or F protein derived from the MV Edmonston strain (de Swart et al., 1998). By incubating human serum on these cells for several days, MV glyco...

Functional and Structural Characterization of Neutralizing Epitopes of Measles Virus Hemagglutinin Protein

“…individuals (9)(10)(11). A key finding in the present study is that the antigenic site vi, which is unrelated to receptor binding but probably involved in the formation of a higher-order H-F protein oligomeric structure (34,36,49), is a major neutralizing epitope that is conserved among different genotype strains.…”

“…Binding of the H protein to a receptor triggers F protein-mediated membrane fusion between the virus envelope and the host cell plasma membrane. Although neutralizing Abs directed against each of the viral envelope glycoproteins are elicited, H protein-specific Abs mainly account for the protection against MV infection (9)(10)(11). All measles vaccines consist of live attenuated MV strains isolated about a half a century ago.…”

The Receptor-Binding Site of the Measles Virus Hemagglutinin Protein Itself Constitutes a Conserved Neutralizing Epitope

“…The signaling lymphocyte activation molecule (SLAM) on a subset of immune cells and nectin4 at adherens junctions are the principal receptors for MV (1)(2)(3)(4). The H and F proteins are both neutralizing targets, but greater amounts of antibodies (Abs) are elicited against the H protein than the F protein, and the H protein-specific antibodies mainly contribute to neutralization of MV infection in vivo (5)(6)(7)(8). All the available data suggest that measles eradication is biologically feasible (9,10), and one of the major factors that would ensure measles eradication is the single-serotype nature of MV.…”

Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens

“…Neutralizing antibody titers above 120 are considered protective, even in the absence of T cell-mediated immunity, and conversely, a morbillivirus infection-induced T cell response alone is sufficient for protection from reinfection (42)(43)(44). Previous studies demonstrated that the H protein is by far the most important target for neutralizing antibodies (17,45,46), so many vaccine development approaches have chosen to focus on this protein. However, the increasing diversity of CDV H proteins among circulating strains from different geographic regions compared to the vaccine strain H protein suggests variation in antigenic epitopes (33,47).…”