Use Fractional Dosing to Speed Vaccination and Save Lives

I’ve been shouting about fractional dosing since January, most recently with my post A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca and the associated paper with Michael Kremer and co-authors. Yesterday we saw some big movement. Writing in Nature Medicine, WHO epidemiologists Benjamin Cowling and Wey Wen Lim and evolutionary biologist Sarah Cobey title a correspondence:

Fractionation of COVID-19 vaccine doses could extend limited supplies and reduce mortality.

Exactly so. They write:

Dose-finding studies indicate that fractional doses of mRNA vaccines could still elicit a robust immune response to COVID-192,3. In a non-randomized open-label phase 1/2 trial of the BNT162b2 vaccine, doses as low as one third (10 μg) of the full dose produced antibody and cellular immune responses comparable to those achieved with the full dose of 30 μg (ref. 4). Specifically, the geometric mean titer of neutralizing antibodies 21 days after the second vaccine dose was 166 for the group that received 10 μg, almost the same as the geometric mean titer of 161 for the group that received 30 μg, and 63 days after the second dose, these titers were 181 and 133, respectively4. For the mRNA-1273 vaccine, a dose of 25 μg conferred geometric mean PRNT80 titers (the inverse of the concentration of serum needed to reduce the number of plaques by 80% in a plaque reduction neutralization test) of 340 at 14 days after the second dose, compared with a value of 654 for the group that received the standard dose of 100 μg (ref. 5). According to the model proposed by Khoury et al.6, if vaccine efficacy at the full dose is 95%, a reduction in dose that led to as much as a halving in the post-vaccination geometric mean titer could still be in the range of 85–90%. Although other components of the immune response may also contribute to efficacy, these dose-finding data are at least indicative of the potential for further exploration of fractionation as a dose-sparing strategy. Durability of responses after fractional doses should also be explored.

…Concerns about the evolution of vaccine resistance have been posited as a potential drawback of dose-sparing strategies. However, vaccines that provide protection against clinical disease seem to also reduce transmission, which indicates that expanding partial vaccination coverage could reduce the incidence of infection. As described in a recent paper, lower prevalence should slow, not accelerate, the emergence and spread of new SARS-CoV-2 variants8.

…In conclusion, fractionated doses could provide a feasible solution that extends limited supplies of vaccines against COVID-19, which is a major challenge for low- and middle-income countries.

Also a new paper in preprint just showed that 1/4 doses of Moderna create a substantial and lasting immune response on par with that from natural infection.

Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 ug Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 ug) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNg-expressing cells.

Finally, an article in Reuters notes that Moderna are preparing to launch a 50 ug dose regimen as a booster and for children. Thus, contrary to some critics of our paper, the technology is ready.

Frankly, governments are way behind on this–they should have been pushing the vaccine manufacturers and funding trials on alternative dosing since at least January. Indeed, imagine how many lives we might have saved had we listened to Operation Warp Speed advisor Moncef Slaoui who advocated for half doses in January. On a world scale, we could have vaccinated tens even hundreds of millions more people by now had we ramped up fractional dosing.

At this point, it’s my view that there is enough knowledge to justify rolling out alternative dosing in any hot spot or in any country worried about outbreaks. Roll it out in a randomized fashion (as Kominers and I discussed in the context of the US vaccination rollout) to study it in real time but start the roll out now. Lives can be saved if we speed up vaccination, especially of the best vaccines we have, the mRNAs. Moderna and Pfizer have together pledged to deliver (mostly Pfizer and mostly through the US) some 250m vaccine doses to COVAX in 2021 for delivery to less developed countries. If we go to half-doses that becomes 500m doses–a life saver. And recall these points made earlier:

Judging by neutralizing antibodies, a 50 ug dose of, for example, Moderna looks to be more effective than standard dosing of many other vaccines including AZ and J&J and much better than others such as Sinovac. Thus alternative dosing is a way to *increase* the quality of vaccine for many people.

A 50 ug dose vaccine available today is much higher quality than a 100 ug dose vaccine available one year from now.

If we have the will, we can increase vaccine supply very rapidly.

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