Another mRNA booster or not?

A fourth mRNA dose has been underway in Israel for a few months now. The U.K. recently started a fourth dose for people over 75 years old and coined it “spring boosters.” In Germany, those over 70 years old are eligible for a fourth shot of the mRNA series.

In the U.S., Pfizer announced they were seeking an EUA for a fourth dosage for people 65 years or older. Moderna is also seeking approval for a fourth dose for everyone. (J&J folks are still kept in the dark; see my note at the end of this post.) On April 6, the FDA external advisory group, VRBPAC, will meet to discuss considerations for future doses. No votes will be taken and no individual vaccine applications will be considered.

So, this begs some questions:

1. How well are third doses working?

2. Is the fourth dose effective in Israel?

3. And, most importantly, what’s our long-term game plan?

Here are some answers.

A third dose is critical

There is no question that a third dose of the mRNA series is critical. The combination of serious immune evasion from Omicron coupled with waning protection over time really impacted vaccine effectiveness. As a recent Nature article pointed out, a third dose against Omicron is about equal to a second dose against Delta. Omicron really made us step up our game.

Figure from Shen, X. Boosting immunity to Omicron. Nat Med 28, 445–446 (2022).

How are boosters holding up over time?

The best real-time data to follow on vaccine effectiveness (VE) over time is in the U.K. The U.K. Health Security Agency currently has follow-up data for 15 weeks after the third dose. In their latest report (published yesterday), it’s clear that VE against infection is significantly waning over time after a third dose. VE continues to be the same for BA.1 compared to BA.2.

(UK Health Security Agency)

VE against hospitalization is holding up much better. But even that is slightly decreasing over time. Moderna seems to be holding up better, but in the U.K. not many get the Moderna vaccine, so there is great uncertainty around these statistics and not much follow-up time.

(UK Health Security Agency)

While this data is powerful, 15 weeks of follow-up data isn’t very helpful in the U.S. because many Americans are coming up on six months (~24 weeks) after their third dose.

Thankfully, a recent study assessed the durability of a Moderna third dose after 6 months. They found a 6.3-fold decrease in neutralizing antibodies. Importantly there was still detectable protection. (This was a much different story than for the second dose which showed a 7.8-fold decrease and very little detectable protection after 7 months.) Although the decline after a third dose was slower, there was still a meaningful decline. In other words, the durability trend of the third shot is not ideal.

Figure from N Engl J Med 2022; 386:1088-1091. DOI: 10.1056/NEJMc2119912

The CDC also published data on VE against Omicron over time in the U.S. They found significantly waning protection against emergency department/urgent care visits. VE against hospitalization was decreasing a little but largely held up 5 months after the third dose.

Figure created by Dr Katelyn Jetelina (YLE) using data from Ferdinands et al. in MMWR Here

Older adults

The aforementioned studies pooled everyone. But we know VE among older adults is suboptimal. And, because of this, we’ve seen severe breakthrough infections at a much higher rate among 65+ year olds. The Kaiser Family Foundation found that among severe breakthrough infections, 69% were among older adults. So it’s imperative that we track VE among this group specifically.

(Kaiser Family Foundation)

The Lancet recently published a small study that assessed the durability of a third dose among people aged 76 to 96 years old. Study participants were followed for 10 months after their second Pfizer dose and 4.5 months after their third Pfizer dose. They found a third dose was crucial for VE. They also found the third dose half life was 52 days for the Wuhan variant, 64 days for Delta, and 41 days for Omicron. So boosters are waning faster for Omicron. But are largely still protective 4.5 months after the third dose for older adults.

Figure from Vanshylla et al., https://doi.org/10.1016/S1473-3099(22)00135-9

In yesterday’s U.K. report, VE against hospitalization among 65+ year olds was also reported. They assessed VE using three different definitions of hospitalization. In all, the story was the same: Vaccine protection against severe disease is waning slightly among 65+ year olds but not by much.

Figure created by Dr Katelyn Jetelina (YLE) using data from UK Health Security Agency Here

Value of a fourth dose?

Now that Israel has been delivering a fourth dose for some time, we can start assessing the efficacy. The results are absolutely fascinating.

In a preprint, scientists assessed the rates of infection and severe illness after a fourth dose among 1,138,681 Israelis aged 60+ years. They found that after a fourth dose, the rate of infection was 2 times lower and the rate of severe disease was 4 times lower. A fourth booster had a meaningful impact for older adults.

Another published study assessed the effectiveness of a fourth dose among young healthcare workers. They confirmed that antibodies were significantly reduced 5 months after the third dose. But a fourth dose pushed these back up.

Figure from NEJM 10.1056/NEJMc2202542

Importantly, this study found that immunogenicity maxes out at 3 doses. In other words, there was no meaningful increase in the quality of the immune system after a fourth dose among the young population. They also assessed the efficacy of the fourth dose compared to the third dose, and the added benefit was not statistically significant. In other words, the efficacy of a fourth dose was no different from the efficacy of a third dose.

Figure from NEJM 10.1056/NEJMc2202542

Should we get a fourth dose?

This is an incredibly difficult question, and the FDA meeting will be important to follow. They will discuss some key questions:

1. What is the purpose of vaccines: to prevent infection or to prevent severe disease? Vaccines are still doing a great job at the latter.

2. What are the costs/benefits of vaccinating now compared to vaccinating in a few months prior to the fall/winter? In other words, should we wait a few months on the fourth dose and focus efforts on getting everyone the third dose? (Only 44% of Americans have the booster.)

3. Are there scientific results not publicly available, like the effectiveness of variant-specific vaccines? It’s about time we see these.

The FDA may approve a fourth dose for 65+ in the coming weeks. I would be very surprised if they approved another dosage for everyone.

But a fourth dose of the same thing would only be a short-term solution. It’s not practical or sustainable to roll-out mRNA vaccines every couple months given their reactogenicity (i.e., lots of side effects). Also, continuing more of the same may reach a threshold, like we saw in the Israel healthcare study. We really need to figure out our next move. There are a few options:

• Get intranasal vaccines to work (the Iwasaki lab at Yale is working day and night on this);

• Roll out a different mRNA formula, like an Alpha or Omicron specific vaccine;

• Start purposefully integrating a different biotechnology vaccine into the series, like an adjuvanted subunit vaccine; or,

• Push for more innovative second generation vaccines, like a pancoronavirus vaccine.

Whatever the solution, we need government support. With decreased funding it’s clear that we don’t even have enough funds to purchase a fourth dose (regular formula) for everyone. Also, research, development, and innovation will soon fade without financial support. This happened with vaccine innovation after the SARS epidemic. We cannot repeat history and let this happen with SARS-CoV-2, too.

Love, YLE

P.S. I know J&J people are feeling left behind. Data continues to show that a J&J + 1 booster is working as well as the mRNA three dose series. We don’t know why, but there are many hypotheses. For example, the adenovirus biotechnology may lead to greater durability and “affinity maturation”—more sophisticated antibodies over time. Or, this may be a biproduct of mixing vaccine biotechnologies. In short, you do not need a third dose right now. We’re all keeping an eye on the literature.

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“Your Local Epidemiologist (YLE)” is written by Dr. Katelyn Jetelina, MPH PhD—an epidemiologist, biostatistician, professor, researcher, wife, and mom of two little girls. During the day she has a research lab and teaches graduate-level courses, but at night she writes this newsletter. Her main goal is to “translate” the ever-evolving public health science so that people will be well equipped to make evidence-based decisions. This newsletter is free thanks to the generous support of fellow YLE community members. To support the effort, please subscribe here: