What the latest studies show — and what they don’t — about the bivalent boosters’ effectiveness

In early September, the Centers for Disease Control and Prevention (CDC) recommended updated Covid-19 boosters for all Americans 12 and older.

“Update” as the vaccine targets spread: In addition to targeting the initial strain of the virus, the new boosters will also target the spike protein present in the new omicron variant of SARS-CoV-2, BA. 4 and BA.5.

The hope is that the new boosters (called “bivalent,” for both strains) will provide additional protection, allowing the immune system to recognize the highly mutated virus that has gotten better at evading the immune system and re-infecting people.

Back in the fall, that hope was mostly based on modest data showing that the updated boosters increased antibody levels in those who received them. But the big question remains unanswered: In the real world, will the updated boosters prevent more cases of severe disease than the original, monovalent boosters?

Researchers aren’t sure, and are divided on whether it’s worth the $5 billion to update the boosters without better data.

We now have real-world human data on bivalent boosters, along with more carefully controlled laboratory studies. They showed that over the past few months, older people who got a bivalent booster last fall were more likely to have a Covid-related hospitalization or death in the next few months than those who didn’t.

However, this research still tells an incomplete story because the data was collected. Scientists do not yet have clear answers to all questions about boosters.

Here’s the latest available data on vaccine boosters and what they don’t — and how future research needs to change to chart a more precise path.

The good news: Bivalent boosters have helped some people over the age of 65 stay alive and out of the hospital

The data coming out now is very promising, but there is a big caveat.

Let’s start with the results of this new study:

A CDC study published in late December showed that between September 13 and November 18, there were 31 percent fewer emergency room or urgent care visits for Covid-19 among adults 18 and older who received the booster shot than those who received the monovalent vaccine series (using or without one to two additional monovalent booster doses) two to four months before the same time point.

(To Note: People who do not get a bivalent booster are not completely protected. But the longer it is since the last dose of the original vaccine, the more their protection decreases – and the risk increases, especially if they are over 65.)

Different recent CDC publications also show the booster’s protective effect is particularly strong in adults. Americans 65 and older who received a booster dose had 73 percent fewer Covid-19 hospitalizations in the fall than those who received at least two doses of the monovalent vaccine.

Another recently published preprint study of nearly 700,000 Israeli adults 65 and older shows evidence of stronger protection for older adults. In the study, between September 24 and December 12, the bivalent booster reduced hospitalizations by 81 percent and deaths by 86 percent in people who received it compared to those who received at least two doses of the monovalent vaccine.

All of this suggests that people who got the bivalent vaccine last fall did better than those who didn’t — especially if they were 65 or older.

Now, a big caveat that makes these studies difficult to interpret:

All of this data comes from retrospective observational studies – that is, studies that observe people outside of a well-controlled lab setting after an intervention (in this case, a bivalent vaccine) has taken place. People who received or did not receive the bivalent vaccine did not do so at random – they chose themselves into one of the groups.

“The people who choose to get it are very different from the people who choose not to get it,” Shira Doron, an infectious disease doctor at Tufts, said of the vaccine: They also prefer to do other protective measures, such as wearing clothes. mask in crowded places and limit travel or socializing when transmission is high.

In contrast, a randomized clinical trial would randomly assign people to receive the bivalent vaccine or not, regardless of their choice. Because it is stronger to control the lifestyle choices that the participants make, the way the Covid-19 vaccine is studied before it is launched. This is also the method scientists use to evaluate medical interventions.

The lack of randomness is the first thing that makes this data look bad. That is, at least some of the outcome differences found in these studies between bivalent recipients and non-recipients may be due to many factors other than the vaccine itself.

The second thing that makes the data look bad: People who got the bivalent vaccine were not compared to people who got the original vaccine at the same time.

While bivalent boosters are available, older versions of the vaccine are not. This means that in all these studies, people who received bivalent were only comparable to people who received monovalent months before..

It’s not exactly apples to apples – people who got the older vaccine have less protection than those who got the newer one because it’s been longer since the last dose. Meanwhile, the SARS-CoV-2 virus has evolved. Thus, these studies are not necessarily comparing people with the same subvariant.

Better would be an evaluation that compares people who got the bivalent vaccine with people who got the monovalent vaccine at the same time, said Walter Orenstein, an infectious disease physician who is associate director of Emory’s Vaccine Center.

All of these caveats mean that there are important questions that the data cannot answer. Questions like:

• Is the bivalent vaccine really better than the original formulation in preventing severe disease in any group of people?
• How much of the bivalent vaccine’s protection is due to the vaccine itself, and how much is due to lifestyle choices?
• Do people under 65 benefit from getting regular booster shots (bivalent or not)? Or how often should boosters be given now, and to whom?
• Are repeated boosters a good idea for adolescents whose mRNA vaccine is associated with higher rates of myocarditis?

The ambiguity of this question has led to some big debates on what strategy boosters should go forward – and what strategy should be used to evaluate boosters’ effectiveness, both before and after they are rolled out.

More carefully controlled laboratory studies have also not shown a clear method

There are several lab data to suggest updated boosters were worth it. But it is also difficult to interpret.

At least eight lab studies have tried to answer the question of whether this new booster causes higher levels of antibodies against newer strains of Covid-19 – including the latest XBB.1.5 variant, which is the omicron subvariant. In a new issue of the newsletter, Eric Topol, a cardiologist and director of the Scripps Research Translational Institute, wrote that the studies “converged in the bivalent superior neutralizing antibody response against BA.5 … but also against XBB.”

Translation: Bivalent appears to be better at provoking antibodies to the latest variant of SARS-CoV-2.

It’s really promising, but it’s only important if you believe that antibodies are an important part of Covid-19 immunity as protection comes from other parts of the immune system that are more difficult to measure, such as T cells – which is still an open question.

There is also some concern that giving boosters that are updated often reduces their effect. Scientists increasingly suspect that the first strains of germs found in the body (whether from infection or vaccination) provide the most lasting immunity. A new study shows that when variants of the same germ arrive quickly, the immune system will not respond as strongly as it is targeted. This phenomenon is called “imprinting,” and it may mean reduced immunological returns for boosters that are frequently renewed.

Antibodies are the first line of defense against infection. So for people who prioritize preventing mild Covid-19 infections, antibody levels are important. But as the pandemic has progressed, some leading experts say stopping mild infections is no longer a priority. That makes the vaccine’s ability to elicit an antibody response less expensive than it used to be.

One proponent of this is Paul Offit, a vaccine expert and vaccination advocate at Children’s Hospital of Pennsylvania. In the new New England Journal of Medicine editorial, Offit wrote that “we should stop trying to prevent all symptomatic infections in healthy young people by adding vaccines containing mRNA from strains that may disappear months later.”

Doron, a Tufts infectious disease doctor, agrees. “I don’t care about the data showing that it prevents infection,” he said. “I want to see if a booster or a vaccine will prevent severe disease.”

“The most important thing” is to think about what studies we need to do to answer these questions, Doron said. “From a financial point of view, you have to prove that the upgraded version is better. And they certainly haven’t done that,” he said.

“Why are we skipping clinical trials?” asks Daniel Salmon, who directs the Vaccine Safety Institute at the Johns Hopkins University School of Public Health. Although costly, time-consuming, and not representative of real-life situations, achieving randomization would be beneficial because of the importance of vaccine confidence, he said. Given how much the US government has spent on the development of a Covid-19 vaccine, “it’s very difficult for me to hear the economic argument” against investing in this higher evidence, he said.

Generating better types of high-quality data proving the effectiveness of modified vaccines is expensive. The US has spent more than $30 billion to develop and launch a Covid-19 vaccine – and it is unlikely that any iteration of the vaccine will receive the same funding.

In the end, “following science” doesn’t always tell us what to do when science is messy. Even a simple question like “is the booster update worth it” can avoid easy answers. We need to find ways to create a higher level of evidence to support future vaccine revisions – or better walk away.