What if I can’t get my second COVID-19 vaccine on time? What the latest science says

Summary:

  • Just one dose of the Pfizer/BioNTech and Moderna/NIH vaccines can offer significant protection from COVID-19
  • Even if you do get sick, one dose of the vaccine may reduce the chances of getting severely sick (see below for details)
  • We don’t know exactly how long and how strong protection will remain, although there is evidence that protection from one dose will likely not entirely fade immediately
  • Until we know more, it’s best to get your second shot as soon as it’s available and continue protecting yourself and your family against getting sick

After a year of worrying about family members or myself dying or getting very sick from COVID-19 I was so relieved when, one by one, they began getting their vaccines. Although it took some persistence, most older family members who wanted a vaccine were eventually able to get their first shot within a relatively short period of time.

Unfortunately, due to vaccine shortages around the country most of my family members have had their second dose appointments cancelled and re-scheduled several times.

In response to the shortages, the Centers for Disease Control and Prevention (CDC) issued CDC COVID vaccine guidance allowing for more flexibility in timing of the vaccine doses if delaying a second shot in unavoidable.

While the recommended time between COVID-19 vaccines is 21 days for Pfizer/BioNTech and 28 days for Moderna/NIH, the new CDC guidance says that both vaccines may be given as much as six weeks (42 days) after the first dose.

It appears that the thinking behind this new guidance is that having more people get at least some protection from one dose of the vaccine can help slow down the spread and prevent hospitalizations and COVID-19-related deaths.

On the other hand, the Food and Drug Administration (FDA) had issued a seemingly conflicting statement on January 4th in response to growing calls to increase the time between doses. It states that “suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence”

So what gives? Why is there so much conflicting information? And is it OK to delay a second COVID-19 vaccine or not?

Given that I’ll be in the last tier of people to get the vaccine, I’ll probably have issues getting my second dose on time too. I wanted to better understand the science behind the conflicting messages, both for mine and family’s sake. Here’s what I found:

How much protection can one dose of the COVID-19 vaccines give?

Since my most vulnerable family members (thankfully) all have their first shot, I started out by learning more about what that one dose means for them in terms of protection.

Overall, the Pfizer/BioNTech vaccine was shown to be 52.4% effective after just one dose and 95% effective after a second dose. Their clinical trial data shows that in the time between first and second doses, 39 people in the trial tested positive for COVID-19 in the vaccinated group while 82 got sick in the placebo (no COVID-19 vaccine) group. The placebo group also had 4 cases of severe COVID-19 while the vaccinated group had 0.

Side note: The UK’s Joint Committee on Vaccination and Immunisation (JCVI) did their own analysis of the Pfizer/BioNTech data, this time only looking at cases of COVID-19 from 14 days to 28 days after vaccination. This re-analysis brought the vaccine efficiency rate after one dose up to about 90%.

They argue that the time points earlier than 14 days may have included people who had not yet developed enough immunity to COVID-19, or who were already infected. Their post hoc analysis of the trial data has come under scrutiny from the scientific community, however, because it makes several assumptions in the analysis that the trial was not designed to test.

Moderna/NIH efficacy clinical trial data shows vaccine effectiveness of 80.2% in a small sample of about 1000 participants receiving just one dose. In this group, 39 participants tested positive for COVID-19 in the placebo control group compared to 7 in the vaccinated group. Of those, 2 participants who got the vaccine came down with severe COVID-19 compared to 4 from the control group.

Although the group size was too small to make firm conclusions, these results hint at the potential for just one dose of the vaccine to provide significant protection compared to no vaccination. Overall effectiveness of the vaccine in the larger group receiving both doses was 95.6% (86.4% for those 65 and older)

The Moderna study also collected nasal swabs from people without COVID-19 symptoms before their second dose of the vaccine. The aim was to determine if one dose of the vaccine could stop someone from contracting the virus, not just reduce symptoms.

They were able to detect the virus in 14 asymptomatic vaccinated participants versus 38 in the placebo group. Although the data is based on a relatively small sample size (~14,000 people), it suggests that a single dose of the Moderna/NIH vaccine can provide some protection from infection. This is key to slowing down spread and deaths from the virus.

Here is a summary of the data:

What about the recent study from Israel showing that a single shot was 85% effective against symptomatic COVID-19?

You’ve likely seen the headlines about a study conducted in Israel reporting that the Pfizer/BioNTech vaccine is 85% effective at reducing symptomatic COVID-19. The researchers investigated the number of COVID-19 cases by looking at records from healthcare workers at Sheba Medical Center who were unvaccinated vs. those who were vaccinated with one dose. The time points measured were at 1-14 days or 15-28 days after the first dose.

They found 60 cases of COVID-19 in unvaccinated workers vs. 28 and 11 cases at 1-14 days and 15-28 days post vaccination, respectively. The authors point out several limitations of the study, however. Among these were the fact that workers were not actively monitored for COVID-19 and groups were not randomly assigned.

This can result in skewed data since not all cases of COVID-19 may have been detected, and there may be behavioral differences (such as risk behavior, attitudes about COVID-19 etc.) between the vaccinated and unvaccinated groups.

Also, this study was conducted over just one month looking at records from about 9,000 people. The total difference in COVID-19 cases between the two groups (vaccinated vs. unvaccinated) was 20. Given the relatively short time period under inspection, and the small group of people studied, this difference may not be statistically significant.

There were a number of other limitations to the study that I won’t go into since a detailed analysis is beyond the scope of this blog. Suffice it to say, there are a lot of shortcomings in this study and it really shouldn’t be used it to draw any conclusions about dose schedules.

How long after vaccination will I develop immunity to COVID-19?

So let’s say you managed to get your first dose of the Pfizer/BioNTech or Moderna/NIH vaccines. How long might it be before that first dose starts to give you some protection?

According to the CDC, it takes a few weeks for the body to build full protection against getting COVID-19 after vaccination. A hint of this can be seen in data from the Pfizer/BioNTech vaccine study:

The graph above from the Pfizer/BioNTech clinical trial shows cases of Covid-19 any time after the first vaccine dose. If you focus on the magnified part of the graph in the inset, you can see a clear separation between the vaccinated (red line, bottom) and non-vaccinated (blue line, top) groups starting around 12 days or so.

So, the first shot gives some protection against COVID-19 after about two weeks and can stop a person from getting sick in the first place or getting severely sick and dying. But early on, before protection starts to kick in around two weeks later, a person could be still be infected and get COVID-19.

How long does protection from one dose of these COVID-19 vaccines last?

The short answer is, we don’t know.

Most participants in the Pfizer/BioNTech and Moderna/NIH vaccine trials received a second shot 21 or 28 days after their first one. There were a few participants who did not get a second dose but they weren’t followed long or close enough to determine if and when protection starts to fade without a second dose.

Also, even if they had been observed for a longer time, the number of people who got just one shot is just too small to say anything even close to definitive about long-term protection from one dose of the vaccine.

In fact, Pfizer and Moderna released a joint statement saying “the safety and efficacy of the vaccine has not been evaluated on different dosing schedules …there is no data to demonstrate that protection after the first dose is sustained after 21 days”.

It’s also important to point out that some people may not even respond to just one dose of the vaccine at all. This is seen with measles, mumps, rubella (MMR) and chickenpox vaccines, for example. The CDC reports that 5-20% of people who get these vaccines fail to respond to one dose, so a second dose is recommended. Of the people who did not respond to a first dose, about 97-99% respond to the second.

So, what evidence IS there for delaying a second dose of the vaccine?

In terms of delaying a second dose, so far much of the evidence available that even hints that it might be OK to delay a second dose of COVID-19 mRNA vaccines is indirect

For example, AstraZeneca recently announced findings from their vaccine trial showing 76% vaccine efficacy after one dose and a 67% reduced detection of COVID-19 in asymptomatic individuals. Importantly, they found that the protective effect did not decrease over a 3 month period. In fact, a gap of twelve weeks or more between doses appeared to increase protection. The results were released as a preprint in the Lancet journal but have not been peer-reviewed by other scientists.

Past studies on vaccine dosing intervals support the AstraZeneca findings. For example, immune response from the H5N1 vaccine was found to be better at 6 months vs. 21 days. Additionally, many studies report a minimum interval between vaccines is needed improve the immune “boost” from the second dose.

Some experts have cited the data from the AstraZeneca trial in support of being able to delay getting a second dose of the Moderna/NIH and Pfizer/BioNTech beyond the initially indicated schedule. This is a dangerous assumption however, since we are not comparing apples to apples here.

While the Moderna/NIH and Pfizer/BioNTech use a mRNA technology, the Oxford/AstraZeneca vaccine uses a more traditional vaccine technology, a weakened virus. So, we can’t assume the immune system will respond the same way in terms of lasting immunity.

In fact, studies have shown that RNA can be quickly degraded in the body and can stimulate different pathways of the immune system, such as RNA sensors (reviewed here).

What do we know about mRNA vaccine efficacy and durable immune response?

In short: mRNA vaccines have been shown to have long term effectiveness after just one dose in animal studies but human trials have not always shown the same thing. Most of the data available for human trials is from two doses

Although the Pfizer/BioNTech and Moderna/NIH vaccines are the first mRNA vaccines to be approved for human use by the FDA, scientists have been working on therapeutic mRNA technologies since the 90s, with the first clinical trials in the early 2000s.

A handful of mRNA vaccine candidates have been shown to induce strong, lasting immune responses in human clinical trials, however the majority have been tested with two or more doses. Also, one key thing to consider is that these have been very early studies with often no more than 50-100 participants.

A quick search for mRNA vaccine studies in phase 3 or higher on clinicaltrials.gov gives only 6 results. Almost all are related to the current COVID-19 vaccines on the market. So there seems to be little data in human trials regarding the long-term immune response for an mRNA vaccine administered without a second booster dose.

There are several studies showing that mRNA vaccines can offer potent and sustained immunity in animals after only one dose vaccine, however. For example, a study released earlier this month reported high and sustained immune response in mice after a single dose of an mRNA vaccine against SARS-CoV-2. The vaccine was able to offer 100% protection against infection in the lungs, with antibody levels maintained at least 6.5 months.

Of course, by now you’re probably guessing there’s a caveat here. There is. We know from past research that immune responses in humans have not always matched those seen in animal studies. This has been a major challenge getting from early to later clinical studies. For this reason, it’s hard to confidently infer long-term outcomes based on results of animal trials.

What’s the take home message?

The take home message from all of this is that the Pfizer/BioNTech and Moderna/NIH mRNA vaccines appear to induce a good immune response after one dose of the vaccines. But we don’t know exactly how long and how strong will continue after the first shot.

Although there is evidence that protection will likely not entirely fade immediately, until we know more, it’s best to get your second shot as soon as it’s available and continue protecting yourself and your family against getting sick.

In fact, just a few days ago, after being asked about the recent study from Israel, Pfizer’s CEO Albert Bourla reiterated the companies earlier position stating:

“there is no study that shows that you can delay…we do not know what will happen if we do not administer the second, how long this duration of immunity will last… we don’t think it will work with one right now”.

So, take it from the manufacturers, whom you would expect would jump on any evidence that their vaccines are highly effective and give durable immunity, we just don’t have enough good data on this right now.

While it may be unsettling to not have more answers, science is evolving quickly on this front with researchers working around the clock to help us learn more about the virus and the vaccines created to fight it.

Remember, there is a light at the end of the COVID-19 tunnel and we are slowly but surely approaching it.