One objection to dose-stretching policies, such as delaying the second dose or using half-doses, is that this might increase the risk of mutation. While possible, some immunologists and evolution experts are now arguing that dose-stretching will probably reduce mutation risk which is what Tyler and I concluded. Here’s Tyler:
One counter argument is that letting “half-vaccinated” people walk around will induce additional virus mutations. Florian Kramer raises this issue, as do a number of others.
Maybe, but again I wish to see your expected value calculations. And in doing these calculations, keep the following points in mind:
a. It is hard to find vaccines where there is a recommendation of “must give the second dose within 21 days” — are there any?
b. The 21-day (or 28-day) interval between doses was chosen to accelerate the completion of the trial, not because it has magical medical properties.
c. Way back when people were thrilled at the idea of Covid vaccines with possible 60% efficacy, few if any painted that scenario as a nightmare of mutations and otherwise giant monster swarms.
d. You get feedback along the way, including from the UK: “If it turns out that immunity wanes quickly with 1 dose, switch policies!” It is easy enough to apply serological testing to a control group to learn along the way. Yes I know this means egg on the face for public health types and the regulators.
e. Under the status quo, with basically p = 1 we have seen two mutations — the English and the South African — from currently unvaccinated populations. Those mutations are here, and they are likely to overwhelm U.S. health care systems within two months. That not only increases the need for a speedy response, it also indicates the chance of regular mutations from the currently “totally unvaccinated” population is really quite high and the results are really quite dire! If you are so worried about hypothetical mutations from the “half vaccinated” we do need a numerical, expected value calculation comparing it to something we already know has happened and may happen yet again. When doing your comparison, the hurdle you will have to clear here is very high.
(See my Washington Post piece for similar arguments and additional references.).
Now here are evolutionary theorists, immunologists and viral experts Sarah Cobey, Daniel B. Larremore, Yonatan H. Grad, and Marc Lipsitch in an excellent paper that first reviews the case for first doses first and then addresses the escape argument. They make several interrelated arguments that a one-dose strategy will reduce transmission, reduce prevalence, and reduce severity and that all of these effects reduce mutation risk.
The arguments above suggest that, thanks to at least some effect on transmission from one dose, widespread use of a single dose of mRNA vaccines will likely reduce infection prevalence…
The reduced transmission and lower prevalence have several effects that individually and together tend to reduce the probability that variants with a fitness advantage such as immune escape will arise and spread (Wen, Malani, and Cobey 2020). The first is that with fewer infected hosts, there are fewer opportunities for new mutations to arise—reducing available genetic variation on which selection can act. Although substitutions that reduce antibody binding were documented before vaccine rollout and are thus relatively common, adaptive evolution is facilitated by the appearance of mutations and other rearrangements that increase the fitness benefit of other mutations (Gong, Suchard, and Bloom 2013; N. C. Wu et al. 2013; Starr and Thornton 2016). The global population size of SARS-CoV-2 is enormous, but the space of possible mutations is larger, and lowering prevalence helps constrain this exploration. Other benefits arise when a small fraction of hosts drives most transmission and the effective reproductive number is low. Selection operates less effectively under these conditions: beneficial mutations will more often be lost by chance, and variants with beneficial mutations are less certain to rise to high frequencies in the population (Desai, Fisher, and Murray 2007; Patwa and Wahl 2008; Otto and Whitlock 1997; Desai and Fisher 2007; Kimura 1957). More research is clearly needed to understand the precise impact of vaccination on SARS-CoV-2 evolution, but multiple lines of evidence suggest that vaccination strategies that reduce prevalence would reduce rather than accelerate the rate of adaptation, including antigenic evolution, and thus incidence over the long term.
In evaluating the potential impact of expanded coverage from dose sparing on the transmission of escape variants, it is necessary to compare the alternative scenario, where fewer individuals are vaccinated (but a larger proportion receive two doses) and more people recover from natural infection. Immunity developing during the course of natural infection, and the immune response that inhibits repeat infection, also impose selection pressure. Although natural infection involves immune responses to a broader set of antibody and T cell targets compared to vaccination, antibodies to the spike protein are likely a major component of protection after either kind of exposure (Addetia et al. 2020; Zost et al. 2020; Steffen et al. 2020), and genetic variants that escape polyclonal sera after natural infection have already been identified (Weisblum et al. 2020; Andreano et al. 2020). Studies comparing the effectiveness of past infection and vaccination on protection and transmission are ongoing. If protective immunity, and specifically protection against transmission, from natural infection is weaker than that from one dose of vaccination, the rate of spread of escape variants in individuals with infection-induced immunity could be higher than in those with vaccine-induced immunity. In this case, an additional advantage of increasing coverage through dose sparing might be a reduction in the selective pressure from infection-induced immunity.
…In the simplest terms, the concern that dose-sparing strategies will enhance the spread of immune escape mutants postulates that individuals with a single dose of vaccine are those with the intermediate, “just right” level of immunity, more likely to evolve escape variants than those with zero or two doses (Bieniasz 2021; Saad-Roy et al. 2021)….There is no particular reason to believe this is the case. Strong immune responses arising from past infection or vaccination will clearly inhibit viral replication, preventing infection and thus within-host adaptation…. Past work on influenza has found no evidence of selection for escape variants during infection in vaccinated hosts (Debbink et al. 2017). Instead, evidence suggests that it is immunocompromised hosts with prolonged influenza infections and high viral loads whose viral populations show high diversity and potentially adaptation (Xue et al. 2017, 2018), a phenomenon also seen with SARS-CoV-2 (Choi et al. 2020; Kemp et al. 2020; Ko et al. 2021). It seems likely, given its impact on disease, that vaccination could shorten such infections, and there is limited evidence already that vaccination reduces the amount of virus present in those who do become infected post-vaccination (Levine-Tiefenbrun et al. 2021).
I also very much agree with these more general points:
The pandemic forces difficult choices under scientific uncertainty. There is a risk that appeals to improve the scientific basis of decision-making will inadvertently equate the absence of precise information about a particular scenario with complete ignorance, and thereby dismiss decades of accumulated and relevant scientific knowledge. Concerns about vaccine-induced evolution are often associated with worry about departing from the precise dosing intervals used in clinical trials. Although other intervals were investigated in earlier immunogenicity studies, for mRNA vaccines, these intervals were partly chosen for speed and have not been completely optimized. They are not the only information on immune responses. Indeed, arguments that vaccine efficacy below 95% would be unacceptable under dose sparing of mRNA vaccines imply that campaigns with the other vaccines estimated to have a lower efficacy pose similar problems. Yet few would advocate these vaccines should be withheld in the thick of a pandemic, or roll outs slowed to increase the number of doses that can be given to a smaller group of people. We urge careful consideration of scientific evidence to minimize lives lost.
The mayor of Detroit has turned down an allocation of the J&J vaccine.
Detroit Mayor Mike Duggan declined an initial allocation of the newly authorized Johnson & Johnson Covid-19 vaccine….”So, Johnson & Johnson is a very good vaccine. Moderna and Pfizer are the best. And I am going to do everything I can to make sure the residents of the city of Detroit get the best,” Duggan said during a news conference Thursday.
Sigh. What an error. Note, however, that the Detroit Mayor rejecting the J&J vaccine is exactly what the FDA has done with the AstraZeneca vaccine. Moreover none other than Anthony Fauci made exactly the same argument about AstraZeneca (an argument I criticized at the time):
But even if the vaccine ends up being approved, it will probably only have an efficacy of 60 to 70 percent. “What are you going to do with the 70 percent when you’ve got two (vaccines) that are 95 percent? Who are you going to give a vaccine like that to?” Anthony Fauci, the leading American expert on vaccines, recently wondered.
To be clear, I don’t blame Fauci for the actions of Detroit Mayor Mike Duggan. Duggan would probably have said the same had Fauci never made his error. Indeed, perhaps you might even read this as excusing Duggan (if even Fauci, “the leading American expert on vaccines”, could make this error then…).
Still, Fauci’s error has been much more costly for the United States.
Hat tip: JF.
Canada’s National Advisory Committee on Immunization (NACI), a scientific advisory group to the government, has made a forceful and dramatic statement strongly favoring First Doses First (delay the second dose.) This is a very big deal for the entire world. Basically NACI have endorsed everything that Tyler and I have said on First Doses First since my first post tentatively raised the issue on December 8. I am going to quote this statement extensively since it’s an excellent summary. No indentation.
Based on emerging evidence of the protection provided by the first dose of a two dose series for COVID-19 vaccines currently authorized in Canada, NACI recommends that in the context of limited COVID-19 vaccine supply jurisdictions should maximize the number of individuals benefiting from the first dose of vaccine by extending the second dose of COVID-19 vaccine up to four months after the first. NACI will continue to monitor the evidence on effectiveness of an extended dose interval and will adjust recommendations as needed. (Strong NACI Recommendation)
- In addition to emerging population-based data, this recommendation is based on expert opinion and the public health principles of equity, ethics, accessibility, feasibility, immunological vaccine principles, and the perspective that, within a global pandemic setting, reducing the risk of severe disease outcomes at the population-level will have the greatest impact. Current evidence suggests high vaccine effectiveness against symptomatic disease and hospitalization for several weeks after the first dose, including among older populations.
- By implementing an extended four month interval strategy, Canada will be able to provide access to first doses of highly efficacious vaccines to more individuals earlier which is expected to increase health equity faster. Canada has secured enough vaccines to ensure that a second dose will be available to every adult.
- As a general vaccination principle, interruption of a vaccine series resulting in an extended interval between doses does not require restarting the vaccine series. Principles of immunology, vaccine science, and historical examples demonstrate that delays between doses do not result in a reduction in final antibody concentrations nor a reduction in durability of memory response for most multi-dose products.
- Assessment of available data on efficacy and effectiveness of a single dose of mRNA vaccine was a critical factor in assessing the impact of a delayed second dose at this time. The two available clinical trials for mRNA vaccines (Pfizer-BioNTech and Moderna) provide evidence that indicates that efficacy against symptomatic disease begins as early as 12 to 14 days after the first dose of the mRNA vaccine. Excluding the first 14 days before vaccines are expected to offer protection, both vaccines showed an efficacy of 92% up until the second dose (most second doses were administered at 19-42 days in the trials). Recently, real world vaccine effectiveness data presented to or reviewed by NACI assessing PCR-positive COVID-19 disease and/or infection from Quebec, British Columbia, Israel, the United Kingdom and the United States support good effectiveness (generally 70-80%, depending on the methodology used and outcomes assessed) from a single dose of mRNA vaccines (for up to two months in some studies). While studies have not yet collected four months of data on effectiveness of the first dose, the first two months of population-based effectiveness data are showing sustained and high levels of protection. These data include studies in health care workers, long term care residents, elderly populations and the general public. While this is somewhat lower than the efficacy demonstrated after one dose in clinical trials, it is important to note that vaccine effectiveness in a general population setting is typically lower than efficacy from the controlled setting of a clinical trial, and this is expected to be the case after series completion as well.
- Published data from the AstraZeneca clinical trial indicated that delaying the second dose to ≥ 12 weeks resulted in a better efficacy against symptomatic disease compared to shorter intervals between doses.
- The duration of protection from one or two doses of COVID-19 vaccines is currently unknown. Experience with other multi-dose vaccines after a single dose suggests persistent protection could last for six months or longer in adolescents and adults. Longer-term follow-up of clinical trial participants and those receiving vaccination in public programs will assist in determining the duration of protection following both one and two doses of vaccination. NACI will continue to monitor the evidence on effectiveness of an extended interval, which is currently being collected weekly in some Canadian jurisdictions, and will adjust recommendations as needed if concerns emerge about waning protection.
- Although effectiveness after two-doses will be somewhat higher than with one dose, many more people will benefit from immunization when extending the interval between doses in times of vaccine shortage; offering more individuals direct benefit and also the possibility of indirect benefit from increasing population immunity to COVID-19 disease. Everyone is expected to obtain the full benefit of two doses when the second dose is offered after 4 months.
- Internal PHAC modelling reviewed by NACI based on Canadian supply projections suggested that accelerating vaccine coverage by extending dose intervals of mRNA vaccines could have short-term public health benefits in preventing symptomatic disease, hospitalizations, and deaths while vaccine supply is constrained. Even a theoretical scenario analysis in which intervals were extended up to six months and protection was lost at a rate of 4% per week after the first dose also showed that extending the mRNA vaccine dose intervals would still have public health benefits. External modelling results have also suggested that extending dose intervals can avert infections, hospitalizations and deaths.
- The impact on variants of concern by extending the interval between doses is unknown, but there is currently no evidence that an extended interval between doses will either increase or decrease the emergence of variants of concern. COVID-19 mRNA vaccines and AstraZeneca vaccine have shown promising early results against variant B.1.1.7. As effectiveness of the first dose against other variants of concern is emerging, ongoing monitoring will be required.
- Vaccine distribution will be optimized through this strategy, and current vaccine supply projections will work well with an extended dose strategy that aims to immunize as many Canadians as efficiently as possible. Extending the dose intervals for mRNA vaccines up to four months has the potential to result in rapid immunization and protection of a large proportion of the Canadian population….
That is the topic of my latest Bloomberg column, here is one excerpt:
To be clear, public health officials are encouraging additional vaccinations. But they don’t seem to realize how much their own ostensibly “careful” rhetoric makes vaccination sound unappealing. “Not talking up the vaccines” is a sin of omission, not a sin of commission, and so it is tolerated and is not a major issue for public debate.
Should public officials be allowed, indeed encouraged, to treat sins of commission and omission so differently, as private citizens (myself included) typically do?
I live near Arlington National Cemetery, where approximately 400,000 veterans (and family members) are buried. I suspect they would not care so much whether their deaths were the result of errors of commission or omission. Did a commanding general order a hill to be charged that should have been left alone? Or did he make the mistake of not charging a hill that could have been taken?
Most citizens care about the total number of military casualties from a battle and are only modestly concerned about the details of the mistakes that caused them. That seems like the right and rational attitude. Perhaps it is also the correct attitude for the war against the coronavirus — that is, an overriding concern with casualties and outcomes, regardless of the kind of error that led to them.
The Canadian province of British Columbia has moved to First Doses First (as I suggested they would) with a four month (not three as in Great Britain) delay on the second dose. Quebec is already using FDF. I believe that the rest of Canada will follow shortly:
Also on Monday, the province announced it is extending the time between first and second doses of COVID-19 vaccine to four months. The change, as well as Health Canada’s approval of a third vaccine, means every eligible person in B.C. will receive the first dose of their vaccine by mid- to late July.
Provincial Health Officer Dr. Bonnie Henry said data from the B.C. Centre for Disease Control — and countries around the world such as the United Kingdom and New Zealand — shows “miraculous” protection of at least 90 per cent from the first dose of a Moderna or Pfizer-BioNTech vaccine.
She said the National Advisory Committee on Immunization is expected to issue a statement to align with B.C.’s decision, which frees up 70,000 doses for younger age groups.
“This is amazing news,” said Henry. “These vaccines work, they give a very high level of protection and that protection lasts for many months.”
As I wrote earlier:
… first doses first will save lives in the US but delaying the second dose and other dose-stretching policies are even more vital in countries [such as Canada] where vaccines supplies are more limited than in the United States.
Meanwhile in the United States we are vaccinating relatively quickly but in the last week we have given out more second doses than first doses. Overall, we have given out 25 million second doses–under first doses first we would have vaccinated 25 million more people benefiting them and the unvaccinated by lowering transmission rates.
The US FDA is not following the science.
A new study from Public Health England shows that both the Pfizer and AstraZeneca vaccine work well from the first dose. If that sounds familiar it’s because the results are similar to those found in Scotland. The results cover all adults in England aged 70 years and older (over 7.5 million people).
Vaccination with either a single dose of BNT162b2 or ChAdOx1 COVID-19 vaccination was associated with a significant reduction in symptomatic SARS-CoV2 positive cases in older adults with even greater protection against severe disease [approximately 80% effective at preventing hospitalisation, AT] . Both vaccines show similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 provides further protection against symptomatic disease but second doses of ChAdOx1 have not yet been rolled out in England. There is a clear effect of the vaccines against the UK variant of concern.
Score three for the land of Reverend Bayes: first doses first, approve AstraZeneca, approve AstraZeneca for the elderly.
The US FDA is not following the science.
Canada has approved the AstraZeneca vaccine. The US has not. The US has paid for an AstraZeneca factory in Baltimore and stockpiled millions of doses. The US should lease the factory to Canada or simply make the doses available for export. The same factory will also produce the J&J vaccine so it’s possible that there is some small opportunity cost. Exporting vaccine to our close ally, trading partner, and neighbor, however, would create significant political, economic, and health benefits for the United States.
More generally, the US is focused on vaccinating its residents first. That’s understandable. But step two is vaccinating the world. The Kremer team advocated going big on vaccine capacity for two reasons. First, we needed a lot of capacity to vaccinate the US fast and fast was valuable. Second, going big meant that the US could vaccinate its population quickly but then have that capacity available to vaccinate the rest of the world.
Contrary to what many people feared, Operation Warp Speed hasn’t taken doses from the rest of the world, Operation Warp Speed has built the infrastructure to deliver doses to the rest of the world. Our motto in advising governments and NGOs was ‘Capacity is the antidote to conflicts over distribution.‘
The United States will soon be the first big country with a fully vaccinated population. The US will then have a chance to lead the world into the post-pandemic era with a “Biden plan” for world vaccination akin to the Mashall Plan.
Invest more. Vaccinate the world. End the pandemic.
Start with Canada.
Should you take a less efficacious vaccine or wait for a more efficacious vaccine? The individual and social incentives are in conflict. For society as a whole it’s typically much better if everyone takes the less efficacious vaccine sooner. We show one example of this in the supplementary material to the Science Paper with details under different scenarios in a forthcoming paper but the intuition is clear. Herd immunity is herd immunity. In the final analysis what you care about is not your chances of overcoming the disease if challenged (the vaccine efficacy) but your chances of overcoming the disease if challenged times the probability of being challenged. Herd immunity means pushing the latter number close to zero which is more important than modest differences in efficacy rates.
What about at the individual level? If you have a choice, it’s clearly better to get the more efficacious vaccine, especially since both vaccines are free (the price system has its advantages in clearing markets). But if you have to wait for the more efficacious vaccine, the choice isn’t obvious. Many people in Europe aren’t taking the AstraZeneca vaccine in the hopes of getting an mRNA vaccine later but I think that is a mistake. Don’t fail to wear your seatbelt today because your next car may have airbags. I’d be happy to take the AstraZeneca vaccine today, if only the government would let me.
Moreover, there is little reason to believe that you can’t follow-up the J&J or AstraZeneca vaccine with a mRNA vaccine at a later date.* If we will be taking multiple SARS-COV-2 vaccines over the next 10 years, as seems likely, it really doesn’t matter much which one we get first.
Do yourself and your society a favor by getting whatever vaccine is available.
Everything in this post applies even more strongly to a country making decisions. Buy the vaccine with the earliest delivery date! And don’t forget to consider the Gamaleya, Sinovac and Sinopharm vaccines.
* Multiple shots of adenoviral vector vaccines such as AZ may become less efficacious overtime as people’s bodies recognize the vector.
As the pace of recovery quickens, and most balance sheets continue to look decent, it seems increasingly obvious that $1.9 trillion is too much to spend. We are spending at least $1 trillion too much, with very little investment to show for it, and $1 trillion is a lot of money. Heaven forbid they should make part of the stimulus dependent on future macroeconomic variables, which is what science would suggest.
New CDC school opening guidelines fail to “follow the science.” School reopening is a big, big issue. Overall the blue states are not doing well on it, and the Biden administration is hurting rather than helping.
Vaccine distribution is doing better, with 2.4 million doses distributed per day by the end of this last week. I am less sure how much that is above the previous trajectory. At least originally, Biden was boasting of aspiring to doing one million doses a day, so the presidential grasp of detail is not what pushed us over the edge here.
Those are arguably the three most important issues at the moment, and the overall performance level is not great.
The AstraZeneca vaccine still is not approved, with no sign of an FDA budge in sight. Canada approved it last week, so now there are more than fifteen nations on board. The new data on its performance are quite strong, even for a single dose.
Biden will be appointing an FDA head, but I haven’t heard talk of reform in spite of major and ongoing failures, and some in process reforms in the UK. Is it even permissible to raise the topic of “the deregulations we need”?
The $15 minimum wage idea seems doomed to fail, in any case it was obviously worse than an “indexed by state” approach, even if you hold the Dube-ous view of minimum wage economics.
The emergency facility — a vestige of the Trump administration that was open for only a month in summer 2019 — is being reactivated to hold up to 700 children ages 13 to 17.
By the way, arrests of unaccompanied children at the border are up 50% this month (WSJ). So this problem isn’t going away. Is science being used to structure the incentives properly for these migrants?
That issue aside, immigration is the one policy area where there has been major sustained improvement, and where those improvements are likely to continue.
As far as I know, there is no immediate plan to eliminate or lower the Trump tariffs on Chinese goods.
The (non-scientific) belief in a new era of cooperation with Europe, including in opposition to China, already lies in tatters.
I don’t know if the American military should have bombed Syria, but I do know that it did and I suspect our government also does not know if it should have, not really know in the scientific sense.
I do get that the Biden administration “feels more scientific” to you, and it has the demeanor of a proper establishment, and it offers experts much higher status, and it does not encourage yahoos to storm the Capitol, for which I am very grateful.
But the rather obvious evidence here is that the scientific record is already quite poor.
Singapore has developed a “globally inter-operable” standard based on blockchain technology to facilitate cross-border verification of health documents, such as pre-departure COVID-19 test results, said Minister-in-charge of the Smart Nation Initiative Vivian Balakrishnan on Friday (Feb 26).
Speaking at the Committee of Supply debate for the Prime Minister’s Office, Dr Balakrishnan said that these notarised pre-departure test results will be available on the SingPass mobile app. The Government will also look into extending this to vaccine certificates.
Here is the full story. Of all those sentences and catch phrases, perhaps “Committee of Supply” is my favorite.
The FDA panel voted unanimously to authorize the J&J vaccine. Good. Note, however, that the single-shot J&J vaccine is quite comparable to the first dose of the Pfizer and Moderna vaccines. Yet, few people are demanding that J&J be required to offer a second shot at all, let alone in 3-4 weeks (What about vaccine escape! How long does immunity with a single-shot last! What about the children!). It really is scandalous how these objections to a single-shot have disappeared. This is evidence of what I call magical thinking–an undue focus on the clinical trial design as having incantatory power.
Why did J&J focus on a single-shot? Was this because of “the science”, i.e. something unique about their vaccine? No. J&J focused on a single-shot vaccine for the same pragmatic reasons that I favor First Doses First.
J&J representatives said they chose to begin with the single shot because the World Health Organization and other experts agreed it would be a faster, more effective tool in an emergency. (emphasis added).
My view is that it would be good if the J&J vaccine was followed by a booster–perhaps of some other vaccine–but that it’s individually fine and in fact socially beneficial to get more people protected quickly by delaying the booster for at least 12 weeks to when vaccines are less scarce. I don’t currently see a reason for thinking differently about the Pfizer and Moderna vaccines.
Drugmakers will be offered fast-tracked approvals for innovative medicines in the UK as ministers seek to build on the country’s world-leading approval of a Covid vaccine and attract life sciences companies to invest post-Brexit.
The UK’s medicines regulator will become independent of EU pharmaceutical rulemaking when Britain quits the European Medicines Agency at the end of the year, which means companies will need to apply separately to register drugs.
With ministers eager to try to refashion the UK as a post-Brexit hub for global life sciences, companies with drugs that promise to treat unmet medical needs will be offered help through the development process, including manufacturing, according to three people familiar with the situation.
Under the so-called Innovative Licensing and Access Pathway, companies are set to be offered the same rolling review of data that speeded approval of the Pfizer/BioNTech Covid-19 vaccine ahead of the rest of the world.
Here is more from Sarah Neville at the FT, via J.