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Merck said Monday it will stop developing both of the current formulations of the Covid-19 vaccines the company was working on, citing inadequate immune responses to the shots.

Work will continue on at least one of the vaccines, which is being developed in partnership with the International AIDS Vaccine Initiative (IAVI), to see if using a different route of administration would improve how effective it is.

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The announcement marks a shocking setback for one of the most storied vaccine makers, and will raise tensions around readouts expected soon from other companies, including Johnson & Johnson and the upstart NovaVax.

Merck said it remains committed to research on Covid-19 and will focus on two treatments it is developing. One is an antiviral medicine against SARS-CoV-2, the virus that causes the disease. The other is a medicine aimed at helping hospitalized patients by reducing the immune system’s over-response to the virus; it has already shown promise in clinical studies.

“We’re disappointed by this result,” Nick Kartsonis, a senior vice president for infectious disease and vaccines at Merck Research Laboratories, said in an interview with STAT. “But it also allows us to continue to focus on our therapeutic candidates and move those forward. And, you know, we are open to continue the work to see if we can address the pandemic in any way we can add value.”

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The results from a Phase 1 trial, described briefly in Merck’s press release, were resoundingly disappointing. The hope was that Merck’s vaccines, which were unique because they used viruses that could replicate once they were in the body, would be long-lasting, one-dose vaccines. The virus used for the vaccine being developed with IAVI is the one used in Merck’s successful vaccine against Ebola. The other vaccine used measles virus, a type of vaccine Merck has manufactured for decades.

Both vaccines, however, produced lower levels of antibodies against SARS-CoV, including binding antibodies and neutralizing antibodies, than is seen in the blood of individuals who have recovered from Covid-19.

Kartsonis said it was difficult to compare results from different studies because researchers have used different assays to measure antibody levels. But it appears neither vaccine performed as well as the Pfizer/BioNTech and Moderna vaccines, which resulted in antibody levels several times above those seen in people who have recovered from Covid-19, and the AstraZeneca/Oxford vaccine, which led to antibody levels roughly equivalent to those seen in people who have recovered from Covid-19.

There are biologically plausible explanations for why the vaccine Merck was developing in partnership with IAVI underperformed in the Phase 1 trial, IAVI President Mark Feinberg told STAT. The vaccine was administered by intramuscular injection; an oral or intranasal administration route might work better, he said.

“While these data are disappointing, this is not the end of the program for us,” Feinberg said.

The vaccine Merck and IAVI have been developing uses a virus that infects livestock — vesicular stomatitis virus (VSV) — but is harmless to humans to present the SARS-2 spike protein to the immune system. Spike proteins project off the exterior of the virus. They attach to human cells, specifically cells with ACE-2 receptors, to trigger infection.

For the vaccine to work, Feinberg explained, it needs to be taken up by cells with ACE-2 receptors. But while the nasal passages have lots of cells with these receptors, muscle cells do not.

“So in a way, the vaccine’s ability to initiate the process of infecting target cells …. and eliciting an immune response, was limited potentially by the route of administration,” he said.

“Both individually as IAVI, and we hope through continued collaboration with Merck, we hope to continue to explore opportunities for either alternative routes of administration or additional modifications to the vector,” Feinberg said.

While Feinberg believes that the VSV-vectored Covid-19 vaccine is worth pursuing, the Phase 1 failure puts the Merck program — already at the back of the pack among major vaccine manufacturers — months or longer behind. That will complicate the path to approval for the vaccine if work on it continues because placebo-controlled clinical trials are becoming increasingly harder to conduct.

The alternative path, running clinical trials comparing the vaccine to another that has already been shown to be protective, requires more participants and runs a higher risk of failure given that some of the authorized vaccines are highly effective.

“It’s not going back to the drawing board, because we actually have a large amount of information to support what we think is worth doing next. But we want to be rigorous with ourselves and say, ‘Is what we’re doing adding value to the broader field?'” Feinberg said. “We think that we may have that possibility. But we need to generate the preclinical data that would merit going back into the clinic.”

In normal times, a vaccine manufacturer that had seen several competitors cross the finish line and get their vaccines into use would likely shelve a project — and this one may very well be headed in that direction. But enormous global demand for Covid-19 vaccines and the slower-than-hoped-for speed of vaccine production and rollout may create a different calculus in this situation.

The news is a reminder that developing new vaccines is difficult, and that the world is lucky that the first two — the Moderna and Pfizer/BioNTech shots — were so effective. In fact, long-term expertise in vaccine development has been less of an advantage than one would expect.

During Merck’s first quarter earnings call in April 2020, Roger Perlmutter, the company’s former head of research and development, said that in the past 25 years, there had been only seven new vaccines directed against previously unaddressed human pathogens. Four of those, he said, were developed by Merck.

Moderna had never developed a product of any kind. Nor had BioNTech, which was focusing mainly on experimental treatments for cancer. Pfizer sold the best-selling vaccine in the world, Prevnar 13, for the pneumococcus bacteria. Those companies developed vaccines with more than 90% efficacy against symptomatic Covid-19, something experts thought might not happen.

Meanwhile, the AstraZeneca/Oxford vaccine has been effective and is in use in the U.K. and India, though results haven’t been as impressive, reducing symptomatic infections by less than 70%. Sanofi, one of the world’s other vaccine makers, said in December that a setback in its early trials would push the delivery of its vaccine from the first half of this year to the second.

Experts have said that multiple vaccines will be needed to vaccinate everyone in the world. According to the World Health Organization, there are 64 potential vaccines in clinical development, including more than a dozen in the late stages of development.

Results from a U.S. trial testing a single dose of Johnson & Johnson’s vaccine are expected any day.

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