A pulmonary influenza virus infection in SCID mice can be cured by treatment with hemagglutinin-specific antibodies that display very low virus-neutralizing activity in vitro

Abstract

We have previously shown that a pulmonary influenza virus infection in SCID mice can be cured by treatment with monoclonal antibodies (MAbs) specific for the viral transmembrane protein hemagglutinin (HA) but not for matrix 2. Since both types of MAbs react with infected cells but only the former neutralizes the virus, it appeared that passive MAbs cured by neutralization of progeny virus rather than reaction with infected host cells. To prove this, we selected a set of four HA-specific MAbs, all of the immunoglobulin G2a isotype, which reacted well with native HA expressed on infected cells yet differed greatly (>10,000-fold) in virus neutralization (VN) activity in vitro, apparently because of differences in antibody avidity and accessibility of the respective determinants on the HA of mature virions. Since the VN activities of these MAbs in vitro were differentially enhanced by serum components, we determined their prophylactic activities in vivo and used them as measures of their actual VN activities in vivo. The comparison of therapeutic and prophylactic activities indicated that these MAbs cured the infection to a greater extent by VN activity (which was greatly enhanced in vivo) and to a lesser extent by reaction with infected host cells. Neither complement- nor NK cell-dependent mechanisms were involved in the MAb-mediated virus clearance.

Neutralizing antiviral antibody responses

“…The VSV protection data are in accordance with the prophylactic antibody dose against numerous viruses, including rabies virus, Ebola virus, coronavirus, and mouse influenza virus (3 µg/ml, 5-15 µg/ml, 5-25 µg/ml, and 1-20 µg/ml, respectively) (Dietzschold et al, 1990;Lamarre and Talbot, 1995;Mozdzanowska et al, 1997;Wilson et al, 2000a). Surprisingly, at a concentration of 30 µg/ml, some Ebola virus-specific antibodies protected 100% of experimental animals even when treatment was started one day post virus exposure.…”

The antiviral activity of antibodies in vitro and in vivo

“…Elegant studies show that SCID mice infected with influenza A for 1 day can be cured using neutralizing mAbs to viral HA with a close correlation between prophylactic and curative activity (Mozdzanowska et al, 1997). The data suggest that the curative effect is mainly due to the neutralizing activity of antibody against free virus, with some contribution from activity against infected cells.…”

“…A detailed study (Mozdzanowska et al, 1997) has compared the in vitro neutralization and in vivo protective activities of a number of mAbs to influenza virus HA. The mAbs were chosen to have a range of neutralizing activities.…”

Virus-Induced Maturation and Activation of Autoreactive Memory B Cells

“…To examine the magnitude of the HA-specific memory B cell response at the level of serum antibody, we measured the ability of serum antibodies obtained after secondary virus immunization of HA104 and non-tg(BALB/c) mice to inhibit hemagglutination (HI assay). The ability of antibodies to neutralize virus-induced hemagglutination in vitro requires B cell recognition of conformation-dependent epitopes on the HA and correlates with the ability of antibodies to protect against viral infection (49,50). As shown in Fig.…”