Thread by @veeslerlab

Can we correlate #SARSCoV2 spike (S) biochemical properties with the specificity, magnitude & quality of antibody responses? Put another way, how to make a good #CovidVaccine ?

@johnbowenbio led the charge to answer these questions

@HHMINEWS

1/21

biorxiv.org/content/10.110…

We compared antibody responses elicited by 6 #CovidVaccine distributed globally: Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, AstraZeneca AZD1222, Gamaleya Sputnik V and Sinopharm BBIBP-CorV, after 2 doses, Janssen Ad26.COV2.S after 1 dose, and human convalescent plasma

2/21

Prefusion S/S2, RBD & NTD antibody binding titers were highest after 2 doses of mRNA-1273 or BNT162b2 and lowest for 1 dose of Ad26.COV2.S. The other 2 dose vaccines and #SARSCoV2 infection resulted in intermediate binding titers.

3/21

mRNA-1273 and BNT162b2 elicited antibodies with 5-fold greater prefusion relative to postfusion S2 binding titers, likely due to the ‘2P’ prefusion-stabilizing S mutations developed by @McLellan_Lab @WardLab1

4/22

pnas.org/content/114/35…

Conversely, natural infection or vaccination with AZD1222, Sputnik V or BBIBP-CorV, which do not contain prefusion-stabilizing S mutations, induced comparable prefusion and postfusion S2 binding titers

5/22

Infection and BBIBP-CorV vaccination induced more postfusion S2 than RBD or NTD antibodies, likely due to S1 shedding and S2 refolding to postfusion on virions/cells, or to β-propiolactone inactivation for BBIBP-CorV (shown by @GroupZhang).

6/22

sciencedirect.com/science/articl…

Prefusion S binding titers in infected and subsequently vaccinated individuals increased by ~2 logs for BNT162b2 and ~1 log for Ad26.COV2.S & AZD1222 compared to pre-vaccination titers.

7/22

Infection/vaccination with BNT162b2 or Ad26.COV2.S induced greater prefusion than postfusion S2 binding titers whereas AZD1222 resulted in similar responses. Lack of prefusion-stabilizing mutations in AZD1222 might explain this due to the metastable nature of the S trimer.

8/22

mRNA-1273 and BNT162b2 elicited highest plasma neutralizing activity & 1 dose Ad26.COV2.S was weakest. Neutralizing antibody titers for infected/vaccinated rose ~1-2 logs vs matched vaccine wo SARS-CoV-2 infection. Infection-only elicited the most heterogeneous responses.

9/22

There is strong positive correlation between in vitro plasma neutralizing activity and the magnitude of antibody binding responses against prefusion S for all vaccines evaluated and for infection-elicited polyclonal antibodies.

10/22

Neutralizing antibody titers were also correlated with NTD- and RBD-directed antibody binding titers, in line with these two domains being the main targets of neutralizing antibodies upon infection or vaccination

11/22

Although prefusion S2 antibody binding titers correlated with neutralization potency, postfusion S2 binding responses did not, indicating that antibodies targeting postfusion S are likely to have a limited impact on reducing viral entry.

12/22

These results emphasize the benefits of favoring the prefusion S conformation to maximize elicited neutralizing antibody titers as well as the higher quality of humoral immune response elicited by vaccination with most platforms compared to natural #SARSCoV2 infection.

13/22

Depletion of prefusion S-targeting antibodies reduced plasma neutralizing activity ≥91% (mRNA-1273), ≥96% (BNT162b2) & ≥89% (AZD1222) whereas depletion using prefusion S2 or postfusion S2 had ~no effect. This shows that neutralizing activity targets prefusion S!

14/22

It is S1 subunit shedding, rather than S2 conformational changes, that leads to a marked loss of potency as most neutralizing antibodies target the RBD and to some extent the NTD. It is thus different from findings for RSV F.

15/22
pnas.org/content/109/8/…
onlinelibrary.wiley.com/doi/10.1002/jm…

Depletion of NTD antibodies reduced neutralization against G614 S but had no effect on inhibition of #Omicron & #Delta pseudoviruses. Depletion of RBD antibodies abrogated variant cross-neutralization, showing that breadth is ~only accounted for by these antibodies.

16/22

These data concur with the marked antigenic variation of the #SARSCoV2 NTD among variants and sarbecoviruses, which is associated with a narrow specificity of NTD neutralizing antibodies, as described by @Dr_MattMcCallum in our group

17/22

sciencedirect.com/science/articl…

And the description of multiple broadly neutralizing sarbecovirus antibodies recognizing distinct RBD antigenic sites such as the S2X259 monoclonal antibody described by @aletortorici in our group

18/22

nature.com/articles/s4158…

#SARSCoV2 S immunogens with additional prefusion-stabilizing mutations (e.g. ‘HexaPro S’ from @McLellan_Lab or ‘VLFIP’ S from @EOSaphire) could yield vaccines eliciting even greater neutralizing antibody titers and in turn enhanced durability and resilience to variants.

19/22

These findings lends even further support to the ongoing clinical development of RBD-based vaccines against #SARSCoV2 and sarbecoviruses for future pandemic preparedness, such as the ones spearheaded by @coronalexington in our group

20/22

sciencedirect.com/science/articl…

Thank you so much @coronalexington Anshu Joshi @sprouse_kaitlin Cameron Stewart @aletortorici
and all our wonderful collaborators including
@SkiClimbSciNick @HelenChuMD @DavideCorti6 and many others not on twitter!

21/22

Finally, @johnbowenbio is applying to several graduate programs across the country.

Catch him if you can!

22/22