Covid Bivalent Vaccines: An Update

 As I suggested in my blog released in February , a new upgraded vaccine has emerged in the form of a bivalent Covid19 product developed by Moderna. This has just been approved by MHRA for use in the UK.

This is something of a milestone in vaccine development, since it is the first approval anywhere in the world of a vaccine designed specifically to mimic the spike protein of the SARS-CoV-2 omicron variants (in this case BA.1). This is not before time – all the current approved vaccines are based on the spike protein of the original Wuhan variant, which was  identified and sequenced by the Chinese way back in early 2020. Many changes have occurred in the structure of the S-Protein since then, making the Omicron variants 'look' quite different to our immune systems, and this has resulted in a considerable reduction in the effectiveness of our vaccines against the virus (although mercifully not so far in their effectiveness against its most serious manifestations).

The new vaccine (Spikevax) purports to be 2nd generation, but I would regard it as a ‘tweaked’ 1st generation product, given that a) 50% of its content is mRNA coding for the original Wuhan strain full S-Protein and b) It contains no sequences coding for other elements of the viral structure besides the S-protein.

The approval of this vaccine now is certainly opportune in that it is in good time for the start of the autumn vaccination season. The UK authorities are becoming increasingly concerned about the dual threat of a Covid resurgence (due to fall-off in immunity since the last round of ‘universal’ boosters) combined with a ‘bad’ flu season, which is also widely anticipated this year.

However, there is an underlying problem with the logistics of delivery which may stop us taking full advantage of this important development.

Moderna have limited production capacity, and have undertaken to supply only 13M doses of this vaccine to UK DOH before year-end. With the expansion of the booster programme to include all over 50s this time round, the number eligible has increased to 26M. This would imply that only half of those offered vaccination before Christmas will get the new vaccine on present estimates.

It was inevitable that this question would arise, given the juxtaposition of the approval announcement and arrangements for autumn boosters, which could certainly have been better managed from a PR point of view. 

Should we all therefore wait until we are specifically offered the updated vaccine, to ensure we get maximum benefit ?

From my own point of view, I would say no – take the vaccine when it's offered and don’t wait until Moderna v2.0 is available. This advice was echoed by DOH yesterday. 

The reason for this is simple – we all need a boost to our immunity now, given it has been at least a year since most of us were last boosted. The ‘old’ vaccines will achieve this perfectly well, and will ensure a good level of protection against serious symptoms and a reduction in the threshold viral dose required for infection. Simple personal precautions, as recommended in my March blog will help minimise your infection risk against Covid, and any of the other respiratory viruses out there this winter, even further.

If you refuse the vaccine this autumn, given the state of our NHS at present, there is no guarantee you will be re-offered the vaccine when more Moderna V2.0 stocks become available, let alone soon enough to ensure your immune protection does not decline to worryingly low levels.

My guess is that every attempt will be made to ensure this does not become a public health issue, which it would if large numbers of those eligible decided to refuse the vaccine. We know that Pfizer has a similar bivalent candidate which is close to approval, and UK Gov is likely to put in advance orders for this to make up the anticipated shortfall with Moderna supplies. 

With any luck, we’ll all get a dose of one or other of the ‘tweaked’ versions sometime this autumn. One thing the current government has shown excellent competence at over the past couple of years is ensuring its population gets vaccinated - I've no doubt that this will continue, despite the current paralysis due to the change of leadership.

By contrast, progress with 2nd generation vaccines (i.e. those with elements targeting other viral structures such as Nucleocapsid) appears disappointingly slow, with one of the 2 principal candidates already having been axed before clinical trials. Let’s hope the tweaked 1st gen. versions manage to keep the virus at bay for a while longer….

Viv

Update 4.9.22: The much-heralded Pfizer bivalent vaccine equivalent has just been approved by MHRA. No indication yet of amount/timing of likely supplies for UK vaccination campaign, but this does augur well for most of those eligible this autumn. Hopefully we will now all get a boost with one or other updated 1st Gen product at some point this winter. Once again, this is a 'whole S' vaccine for both halves of the gene construct, and no attempt has been made to home in on specific regions of the spike protein. 

State of the Art: Update 19.8.23

As of July 2023, the mRNA vaccines are now predominant amongst approved products. Several development candidates have already fallen by the wayside, and the first approved vaccine (Pfizer/ Biontec  Monovalent , original SAS-CoV-2 strain, whole S-protein) was withdrawn in the US in April 2023. Pfizer are seeking approval for a new upgraded bivalent vaccine (BNT162b2) which has whole S-protein sequences for the original strain and for Omicron BA.4 and BA.5 variants. Moderna have already gained approval for their Spikevax bivalent product (1273.222; whole S protein, original strain + BA.1 variant). Their most recent Covid vaccine development (mRNA 1283.222) is a similar bivalent design, but this time with the BA.1 component being receptor binding domain (RBD)- and n-terminal domain (NTD)-directed rather than coding for the whole S protein. Its formulation is also designed to have improved stability such that it can be stored at 4oC rather than deep-frozen. This vaccine is currently trialling at Phase 3 in a head to head comparison with the approved Spikevax. 

In the light of the comments on relative specificity and epitope dilution in the previous section, it will be interesting to see whether this new bivalent design has improved ability to neutralise virus and hence confers better protection against infection in addition to preventing symptomatic disease. Phase 1 & 2 studies have already shown an improved neutralising antibody response; this is more prolonged than for the bivalent whole-S product, as was predicted from animal studies. It is also hoped that 1283.222 will act as an effective booster in pre-vaccinated subjects and maintain high antibody and T-Cell levels for a more prolonged period. If stable at 4oC, it will also provide a major logistic bonus when it comes to storage and distribution, particularly in 3rd world countries.

To my knowledge, there are no mRNA candidates including gene constructs for other viral elements besides S-protein currently undergoing clinical trials.

For more detailed information and a discussion of where we should go with Coronavirus vaccine development in the future, download the publication.

 First Published 16.8.22

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