Thread by @macroliter

Too early to say what this means for @Moderna's #CMV (cytomegalovirus) mRNA vaccine candidate, which is already in Phase III trials. However, this preprint suggests CMV's pentameric gH/gL complex is not important for transplacental infection. #StopCMV 🤰 🧵biorxiv.org/content/10.110…

CMV is notoriously difficult to vaccinate against. When he was still @pfizer, Phil Domitzer & colleagues "threw the book" at rhesus CMV --trying all leading vaccine strategies. The virus still infected, shed and transmitted horizontally just fine. 2/ academic.oup.com/jid/article/22…

Moderna has focused its mRNA vaccine on gB (the viruses' membrane fusion protein, functionally analogous to the S2 domain of a coronavirus' Spike)..and on the receptor binding gH/gL complex that's commonly referred to as "the Pentamer" because it's made up of 5 glycoproteins. 3/

There was initially much excitement about the Pentamer as a vaccine target after Antonio Lanzavecchia and colleagues showed that very tiny amounts of anti-Pentamer antibodies potently neutralized the virus from infecting epithelial cells.. 4/ pnas.org/doi/10.1073/pn…

However, that paper & basically all the other reports showing anti-Pentamer antibodies to be so potent relied upon in vitro infection models, in which the antibodies neutralized cell-free virus from infecting epithelial cell lines. What's the in vivo relevance of that? 🤷 /5

In fact, @StantonRich & co-authors found the Pentamer drives antibody-resistant cell-to-cell spread. Maybe that helps explain why it's so easy to neutralize Pentamer on cell-free virions? Maybe its 'real job' isn't to help cell-free virions enter cells? 6/ pnas.org/doi/full/10.10…

In this scenario, the Pentamer is a "sitting duck" 🦆 on cell-free virions simply because evolution has not demanded it to be "neutralization resistant." Despite the huge importance of the Pentamer for in vitro infectivity, this could make sense. 7/ journals.asm.org/doi/10.1128/JV…

Now, CMV has 2 different gH/gL complexes. The one evolution probably demanded be neutralization resistant is gH/gL/gO, aka 'Trimer." gO fits the bill for a viral entry protein that resists antibodies. >50% of its molecular weight is N-linked glycans! doi.org/10.1128/jvi.02…

Another concern about the Pentamer as a vaccine target is that studies with Rhesus CMV (RhCMV) show that the RhCMV counterparts of two human CMV Pentamer components, UL128 and UL130, counteract important (and unusual) MHC-E restricted T cell responses. 9/ science.org/doi/10.1126/sc…

In any case, Moderna's mRNA vaccine trial does not "read out" until April 2026.. so, we'll have to stay tuned before we find out whether their Pentamer + gB based #CMV vaccine proves efficacious or not. 10/ clinicaltrials.gov/ct2/show/NCT05…

Either way, it remains important to develop effective vaccines against CMV congenital infection & ways to prevent CMV disease in immune-compromised people. 11/

...CMV is a fascinating virus for learning about biology & immunology. But it's the #1 infectious cause of birth defects and is also a common cause of serious, life threatening infections in people who have received solid organ or stem cell transplants. #StopCMV

Ooops.. that'd be @moderna_tx .. (I tagged the wrong @ Moderna in the OP) 13/