Thoughts on the UK’s Gamble With Extending Dosing Intervals and Mixing COVID-19 (Coronavirus) Vaccines

As the United Kingdom (UK) is facing an upsurge of a mutant, highly transmissible variant of the SARS-CoV2 (the virus responsible for COVID-19), British health authorities are taking “creative” measures to fight the pandemic--particularly when faced with a very limited supply of the vaccines.

On December 30, the UK regulator has authorized Oxford University / AstraZeneca’s COVID-19 (coronavirus) vaccine for use by concluding that the vaccine has met its strict standards of safety, quality, and effectiveness. The Joint Committee on Vaccination and Immunization (JCVI) in the UK has recommended prioritizing the high-risk individuals their first dose, although the 2nd dose can be delayed as long as 12 weeks or 3 months, instead of getting it within the first 28 days. This recommendation is a deviation from the 28 days interval between the two doses that were initially defined in the clinical trial protocol for this vaccine.

The reason for this alternative dosing interval is that some trial participants from the AstraZeneca study had taken the 2nd dose at different intervals, and those who took it between 4 to 12 weeks had achieved an 80% efficacy. JCVI thinks that delaying the 2nd dosage will allow the UK to deploy the vaccines to as many people as quickly as possible.

However, JCVI also recommended this alternative dosing regimen for the Pfizer and Modera vaccines. Pfizer/BioNTech’s and Moderna’s phase three studies were only designed to evaluate the vaccine’s safety and efficacy following a two-dose schedule, separated by 21 and 28 days, respectively. Their safety and efficacy have not been evaluated on different dosing schedules. Most of their study volunteers had received the 2nd dose within the window specified in the study design. Although Pfizer’s data showed that partial protection from the vaccine appears to begin as early as 12 days after the 1st dose, two doses of the vaccine are needed for maximum protection against COVID-19—hence an efficacy level of 95% protection. Moreover, there is no data to support that protection after the 1st dose can be sustained after 21 days.

Furthermore, Britain will allow the first dose and second dose for anyone taking the vaccine to be from different vaccine manufacturers, in the event the matching vaccine is not available.

So, will Britain compromise vaccine efficacy by tampering with dosing intervals and mixing up two different vaccines?

Short answer: in theory, it can still work; but there is no guarantee that it wouldn’t end up compromising the outcome!

While data from both mRNA vaccines showed that protection begins as early as 10-12 days after the 1st jab, we don’t have information on how long that initial protection may last. Protection can very well taper off after some time. Also, the levels of antibody protection generated after the 1st dose were not substantial in the clinical trials—which is why we have a 2nd shot. Nowadays, we are also seeing that some individuals are getting COVID-19 after the first dose while waiting on the 2nd one. We don’t even know if a single shot is able to give us protection for more than 28 days. Let’s take a stroll down memory lane and look back at the history to understand similar situations in the past.

We have example cases were mixing up multiple vaccines for the same virus didn’t make a difference one way or another. Take hepatitis A vaccines for instance. There are several vaccine options that are available and multiple studies showed that the hepatitis A vaccines are interchangeable. Interestingly, there is also much flexibility with timing for the booster-dose completion. A similar situation is observed with some hepatitis B vaccines, and the vaccines that are administered for meningococcus group A, C, W, and Y. It is understandable why the UK would make such a recommendation with the COVID-19 (coronavirus vaccines)—because there is precedent for it. However, the flipside has also been apparent where doses from two vaccines weren’t necessarily interchangeable.

Some vaccines that generate protection from the same pathogen can end up having interference when mixed up for the booster-shot. Different kinds of pneumococcal vaccines, which target multiple types of pneumococcal bacteria, for instance, have been shown to have interference based on the order in which the vaccines were received. If a pneumococcal polysaccharide vaccine (PPSV) is given followed by a pneumococcal polysaccharide conjugate vaccine (PCV), there are lower antibody responses or lower protection against some types of bacteria targeted by the PCV vaccine. But when the order is reversed, higher immune protection is triggered.

Vaccine efficacy can be altered when vaccines against same the pathogen are mixed. At the very least, the order in which the vaccines are received may make a huge difference, for good or for worse. In the case of polio vaccines, the oral (Sabin) vaccine is good at generating antibody and T-cell (immune cell) responses for strong protection. The injectable (Salk) form of the polio vaccine (which is a different kind of vaccine from the oral one) is however better at producing mucosal protection in the gut, which is believed to be a better approach to interrupting the spread of the disease in children, even though the injectable version requires multiple doses to achieve immunity. A study showed that in children who had already had the oral Sabin vaccine, a subsequent booster injection of the Salk vaccine was far more effective at producing gut immunity than a second round of the oral vaccine.

At the end of the day, what we want with these vaccines is to generate a strong immune response in the recipients that is an effective one. As long as the immune response generated is strong enough to protect the individuals from future infection, it doesn’t matter how we get to the end result, even if dosing is stretched out and the two doses of the vaccines are different. But the huge caveat here is we do not have any data to support the UK’s recommendation. When we are in the middle of a pandemic, and so much is at stake, should we be gambling with our chance like this?

In any case, the UK’s health authority reserves the right to this decision on alternative dosing intervals. But it would be best to gather data first before introducing a variable. Pfizer has already expressed the importance of doing surveillance efforts on any alternative schedules implemented and to ensure that each recipient is given the maximum possible protection with two doses of the vaccine.

The US health officials will not be following the UK’s lead thankfully. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said that the vaccines will be deployed using the dosing schedules that were tested in Phase 3 studies. This is the right approach given that our regulatory authority authorized the vaccines for emergency use based on evidence generated from the Phase 3 trials.

Let’s be judicious about our choices when we are this close to having a good grip on this COVID-19 disease.

Disclaimer: Vaxtherapy is NOT affiliated with any of the pharma/biotech companies working on COVID-19 vaccines. The purpose of this post is to provide education and awareness from a virologist’s independent perspective based on available facts and data.

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