New coronavirus vaccine research is promising — but it comes with warning signs

First results for trials of biotech firm Moderna’s COVID-19 vaccine have been published in the New England Journal of Medicine. The results of the phase 1 trial show that patients developed a “robust” response to the vaccine, but there are reasons to be concerned. In particular, while the study indicates that there were “no serious adverse events” and the safety was regarded as acceptable for launching the 30,000 person phase 3 trial, that doesn’t mean some people didn’t have issues.

Most of those involved the same kinds of issues that occur commonly in association with flu vaccines: soreness and redness at the injection site, headaches, fever, chills, and muscle aches. Most of these symptoms were mild or nonexistent after the first injection, but this trial involved each person getting two shots and side effects were more pronounced after the second shot. That includes one person who had to be hospitalized with a severe fever of over 103°F.

PHASE 1 TRIAL

This initial phase 1 trial included just 45 participants. That pool was split into three groups, with 15 people receiving injections of 25 micrograms of vaccine, 15 getting a dosage of 100μg, and 15 receiving a maximum dosage of 250μg. Since each patient got a pair of shots, patients in the top group received a total of 500μg.

The injections came four weeks apart, and participants were checked for antibody responses on the days following the injections and at various points over the following month. Samples were tested using ELISA (enzyme-linked immunosorbent assay) and PsVNA (pseudotyped lentivirus reporter neutralization). In general those responses, in the words of researchers, were “robust.”

EFFICACY

The green line on this chart represents a value obtained as the average of 38 convalescent plasma samples from people who had tested positive for COVID-19 and recovered. Though the line is presented as flat over the course of the trial in the chart above, in actuality the convalescent samples were taken at different days over the course of the illness and just represent a kind of average value for people around two months out from their initial bout with SARS-CoV-2.

In general, what the chart shows is that all patients, even those receiving the lowest dose, developed a strong antibody response. However, this really didn’t kick in until the second vaccination. At that point most patients, including all those in the 100μg and 250μg groups, developed antibody levels several times the average of patients who actually had COVID-19.

Even the 25μg group would seem to have more than sufficient levels by this measure, but some other studies have shown that antibodies can drop off within two to three months for COVID-19 patients who have mild or asymptomatic patterns, and the decline seen in the 25μg group here could mean that patients who received this level of vaccine are following this pattern.

And there’s another reason to be concerned about that minimal dose: PsVNA does a better job of singling out the antibodies thought to be most important in neutralizing vaccine activity.

By this measure, those patients receiving the 25μg dose never reached the average level of neutralizing antibody found in the average convalescent plasma. It’s also a bit concerning that the levels in the other groups begin to fall steeply just two weeks after the second vaccination. However, that flat green line for the convalescent group is deceptive. Their values might also have dropped considerably to reach that point, and there’s no clear measure of what level is actually needed for effective immunity.

It’s also worth noting that these lower dosage results appear similar to the Oxford vaccine, with the higher dosage seeming more similar to the results of the SinoVac vaccine (from animal trials).

SAFETY

Over the course of the trial, one patient withdrew after developing a rash around the injection site. That patient was in the lowest-dose 25μg group. The rash proved to be transient, but the patient chose not to continue. For those who remained, about half the patients reported some mild or moderate effects after the first shot. Again, that’s right on par with the effects of annual flu vaccines. After the second shot, more patients developed these milder side effects. That includes 100% of the patients who were in the 100μg group. Three patients in the 250μg group developed symptoms that were considered severe—including fatigue, chills, headache, and the previously mentioned fever.

Going into the phase 3 trial, Moderna will solicit for 30,000 participants, with all those who get the vaccine receiving a 100μg dose. The 250μg dosage, which generated the phase 1 study’s only severe reaction, will not be used going forward. However, considering that 100% of those receiving 100μg developed mild or moderate responses in the phase 1 trial, there are reasons to be concerned that patients may develop severe reactions at the 100μg level during phase 3.

There are also the possibilities of more rare reactions that didn’t appear in the small phase 1 group. For example, Guillain-Barré syndrome may occur with flu vaccines at a rate of around one case per million vaccinations. If something similar was found to occur more frequently, say, at one case per 1,000, the vaccine would likely be judged not safe enough for general use. After all, vaccines are given to millions of healthy people and there are other potential vaccines in the pipeline.

The rapid rise of antibody response following the second injection is good in the sense of protection, but the increase in side effects after this second shot also may mean that it’s not safe to have regular boosters should immunity fade over a period of a few months. Also, the fact that immunity doesn’t seem to be strongly developed until after the “booster” means that even if someone gets their first shot in March, it could be May before they’re really safe.

PHASE 2

Though Moderna is now going ahead with recruiting for the phase 3 study, there is actually a second cohort to what was a phase 1/2 trial testing both safety and immune response. That second cohort contains 300 participants, including a group over 55-years-old. When it reports in a few weeks from now, we should have a better idea on both safety and effectiveness. That group is using injections of 25μg, 50μg, and 100μg, so it would be great to see them come through without any severe reactions—and even better if the 50μg dose turns out to be effective.

MODERNA

As always with Moderna, there are reasons to be concerned. Not only are they using a vaccine technology (mRNA) that has never been trialed on humans before, they’ve been conspicuously leaking out data at each small step. That’s been great for their stock and for backers who, in a coronavirus-free world, might not have seen returns from the company for another decade. It doesn’t necessarily mean they’re pushing too fast or being unsafe, but it does mean that the news from the company bears watching—far more so than for giants like Pfizer. This product could “make” the company.