Anti-HIV therapy: IgG3 is the new kid on the block !
In a fantastic new paper by Chung et al., (2014) that accompanied the paper described in my previous Blog by Yates et al., (2014), the role played by IgG3 has been described very elegantly in the context of 2 HIV vaccines-RV144 and VAX003.
Chung et al., show how IgG3 might be able to fight HIV infection in the absence of viral neutralization.
Background: RV144: ALVAC-HIVvCP1521 prime and recombinant gp120 AIDSVAX B/E boose
VAX003: AIDSVAX B/E bivalent rgp120 given with alum in 7 doses
Results:
* RV144 elicited a polyfunctional antibody response associated with the selective induction of IgG3 antibodies.
* VAX003 elicited a monofunctional antibody response characterized by selection of the functionally inert IgG4 antibody subclass, likely due to repeated administration of gp120 protein vaccination which decreased IgG3 subclass levels.
*RV144 induced both IgG1 and IgG3 antibodies targeting the V2 crown, whereas VAX003 induced an IgG4 antibody response against that epitope.
* Both IgG1 and IgG3 exhibit higher Fc receptor affinity thereby recruiting innate immune effector activity more readily compared to IgG2 and IgG4, both weaker recruiters of Fc receptor-mediated cytolytic activity.
* Specifically, RV144 selectively induced gp120-specific IgG3 antibodies in 58% of vaccinees compared to 38% of VAX003 vaccinees and total IgG3 levels were 4.6x higher in RV144 vaccinees compared with VAX003 vaccinees.
* Depleting IgG3 from the RV144 samples reduced antibody-dependent cellular phagocytosis (ADCP) activity and loss of antibody-dependent cellular cytotoxicity (ADCC) but only reduced ADCP in VAX003 samples.
* Depleting IgG4 increased ADCC and ADCP only in VAX003 but not RV144 samples.
Conclusions from the study:
*IgG3 responses were induced by protein immunization alone and the selection of functional antibody responses is unlikely to be due to viral vector prime alone.
*Viral vector might provide key adjuvanting signals preventing further class-switch recombination to less functional sub-classes during RV144 boosting. Protein immunization in alum (VAX003), in the absence of strong inflammatory priming signals might progressively drive class switch recombination from IgG3 to IgG4.
* IgG3 might be transient due to short half-life.
* IgG3 (about 10% of total circulating antibodies) might co-operate with IgG1 to drive antibody functionality, suggesting that vaccine design should aim to synchronize IgG1 with IgG3 functionalities.
* In spite of different participant profiles (RV144: low risk; VAX003:high risk drug users), it appears that differences in vaccine regimen rather than patient populations account for differences in antibody effector profiles.
Caveats in this study:
Predominant focus on Clade B immunogen.
Future directions:
Determine whether polyfunctional IgG3 Fc-effector function are present in response to gp 120A244 protein (Clade E)
Chung et al., show how IgG3 might be able to fight HIV infection in the absence of viral neutralization.
Background: RV144: ALVAC-HIVvCP1521 prime and recombinant gp120 AIDSVAX B/E boose
VAX003: AIDSVAX B/E bivalent rgp120 given with alum in 7 doses
Results:
* RV144 elicited a polyfunctional antibody response associated with the selective induction of IgG3 antibodies.
* VAX003 elicited a monofunctional antibody response characterized by selection of the functionally inert IgG4 antibody subclass, likely due to repeated administration of gp120 protein vaccination which decreased IgG3 subclass levels.
*RV144 induced both IgG1 and IgG3 antibodies targeting the V2 crown, whereas VAX003 induced an IgG4 antibody response against that epitope.
* Both IgG1 and IgG3 exhibit higher Fc receptor affinity thereby recruiting innate immune effector activity more readily compared to IgG2 and IgG4, both weaker recruiters of Fc receptor-mediated cytolytic activity.
* Specifically, RV144 selectively induced gp120-specific IgG3 antibodies in 58% of vaccinees compared to 38% of VAX003 vaccinees and total IgG3 levels were 4.6x higher in RV144 vaccinees compared with VAX003 vaccinees.
* Depleting IgG3 from the RV144 samples reduced antibody-dependent cellular phagocytosis (ADCP) activity and loss of antibody-dependent cellular cytotoxicity (ADCC) but only reduced ADCP in VAX003 samples.
* Depleting IgG4 increased ADCC and ADCP only in VAX003 but not RV144 samples.
Conclusions from the study:
*IgG3 responses were induced by protein immunization alone and the selection of functional antibody responses is unlikely to be due to viral vector prime alone.
*Viral vector might provide key adjuvanting signals preventing further class-switch recombination to less functional sub-classes during RV144 boosting. Protein immunization in alum (VAX003), in the absence of strong inflammatory priming signals might progressively drive class switch recombination from IgG3 to IgG4.
* IgG3 might be transient due to short half-life.
* IgG3 (about 10% of total circulating antibodies) might co-operate with IgG1 to drive antibody functionality, suggesting that vaccine design should aim to synchronize IgG1 with IgG3 functionalities.
* In spite of different participant profiles (RV144: low risk; VAX003:high risk drug users), it appears that differences in vaccine regimen rather than patient populations account for differences in antibody effector profiles.
Caveats in this study:
Predominant focus on Clade B immunogen.
Future directions:
Determine whether polyfunctional IgG3 Fc-effector function are present in response to gp 120A244 protein (Clade E)
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