| The biotech firm Moderna announced Monday that its Covid-19 vaccine candidate, mRNA-1273, was shown to be 94.5 percent effective in protecting volunteers in a clinical trial against the disease. "This is a pivotal moment in the development of our COVID-19 vaccine candidate," said Stéphane Bancel, CEO of Moderna, in a statement. "This positive interim analysis from our Phase 3 study has given us the first clinical validation that our vaccine can prevent COVID-19 disease, including severe disease." It's more good news following Pfizer and BioNTech's announcement of positive results from their Covid-19 vaccine candidate trial a week ago. But unlike Pfizer and BioNTech, Moderna offered far more information about the recipients of the vaccine, showing its efficacy across different ages and ethnic groups. And its results offer a brighter ray of hope for rolling out a vaccine in 2021 as the United States faces its worst stretch of the pandemic yet, with record numbers of new cases and hospitalizations. The announcements also mean that the world will likely have more than one highly effective vaccine for Covid-19, and the end of the pandemic could be on the horizon. High efficacy also means that fewer people would need to be vaccinated in order to achieve herd immunity, the threshold at which the virus can no longer spread easily from person to person. However, there are some caveats: The results are preliminary, the vaccine requires two doses, there are some side effects, the clinical trial isn't complete, and the findings were announced in a press release instead of a peer-reviewed paper. Moderna did not respond to requests for comment. And while demonstrating high efficacy is important, the road to getting millions of people vaccinated is fraught with logistical challenges. While this is an important result, a lot of difficult work on a Covid-19 vaccine still lies ahead. How Moderna showed that its Covid-19 vaccine works
Moderna's announcement of almost 95 percent efficacy is based on a phase 3 clinical trial. In particular, the results are from the COVE study, conducted in collaboration with the US government's National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA). Phase 3 is where the vaccine is tested against the virus spreading in the real world. Since experimenters can't deliberately infect people, they have to wait and see who gets sick with Covid-19 in their volunteer pool, comparing the group that received the actual vaccine to the group that received the placebo. Moderna's vaccine is administered as two doses spaced four weeks apart. To speed up the process, researchers recruit thousands of volunteers so that the rate of accumulating infections goes up. But it only takes a handful of infections to demonstrate that the vaccine works. "If the vaccine doesn't work at all, and 50 percent of people are in the vaccine group, 50 percent in the placebo group, we expect cases to be evenly split across the groups," explained Natalie Dean, an assistant professor of biostatistics at the University of Florida, in an email. "When the vaccine is working, we observe fewer cases in the vaccine group." According to Moderna, experimenters detected 95 Covid-19 cases, of which 90 cases were in the placebo group compared to five cases in the group that received the actual vaccine. The results show that the virus was spreading among volunteers in the clinical trial but it was drastically lower among those who received Moderna's vaccine. Why Moderna's results, while preliminary, are still important and exciting
There are a number of safeguards in place to ensure that vaccine manufacturers are not gaming the results. In a clinical trial like this, neither the company nor the volunteers know who received the vaccine and who received the placebo. This is known as a double-blind study and is considered the gold standard for clinical research. It's done to prevent either side from changing their behavior or biasing the trial in a deliberate or unconscious way. Someone who knows they received the actual vaccine may engage in riskier behavior, for example, or the company may be tempted to give the vaccine to people already at lower risk of exposure to boost the apparent efficacy. Instead, there's a group of independent scientists appointed by the government known as the Data Safety Monitoring Board (DSMB) that serves as an intermediary between the volunteers and the experimenters. The DSMB knows who received what among the volunteers but doesn't disclose that to the company right away. Instead, the members monitor the trial pool to ensure there are no severe complications and can stop the trial if there are any problems. The DSMB then convenes with the company and experimenters at predetermined checkpoints, namely when a certain number of infections are detected. The recent vaccine announcements from Moderna and from Pfizer and BioNTech both emerged from such a preliminary meeting, both at the 95 infection checkpoint. While these results are not peer-reviewed per se, implicit in these announcements is that a group of independent scientists have verified these results. That's why many scientists who have been paying attention to these clinical trials are so excited about the findings, even though they are preliminary. "The vaccine is on its way, folks, so hang in there, hang tough," Anthony Fauci, director of NIAID, said last week in response to the Pfizer and BioNTech announcement. "We're going to get over this together." Moderna expects the final analysis of its clinical trial to be conducted when 151 Covid-19 infections are confirmed in the trial pool. It's hard to say when it will get that many cases, but given the uncontrolled spread of Covid-19 in the United States, it's likely to happen within the next two months. There are some caveats to Moderna's Covid-19 vaccine results
Moderna's results were announced in a press release — like the Pfizer and BioNTech vaccine results, Moderna's announcement came directly from the company itself. There have been several peer-reviewed interim studies about its mRNA-1273 vaccine, but Monday's efficacy announcement didn't come with any published data. That doesn't mean the results are wrong, but they are only a snapshot in time, and without more details, it's hard to unpack critical nuances needed to interpret them, like what kinds of underlying health conditions influence the efficacy of a vaccine. These for-profit companies also have a financial incentive to play up good news and smooth over any bumps on the road to an approved vaccine. As the trial proceeds, the results could be reinforced or undermined. "When we do finally have a viable Covid-19 immunization, the public needs to be able to trust that it's safe and effective," wrote Vox's Julia Belluz. "And the road to building that confidence isn't paved with preliminary, sparsely detailed news releases that are later overturned when the real work of vetting the vaccines is done." But as mentioned above, the fact that these results have independent validation gives them more weight. So there is cause for optimism and skepticism. Moderna revealed some of the demographics of who is in its trial pool, but more information is still needed; it's unlikely that a vaccine will be equally effective in all groups of people, so it's important to pay close attention to the demographics of who gets sick and who gets protected in a vaccine trial. According to Moderna, the 95 Covid-19 cases were detected in 15 adults over the age of 65 and 20 participants identifying as having a minority background, including 12 Hispanic or Latinx people, four Black or African American people, three Asian American people, and one multiracial person. This shows that the trial recruited a broad spectrum of participants. This is immensely valuable information for public health and can help guide a vaccination strategy. But health officials still need more information about things like preexisting conditions in the trial pool and the amount of exposure to the virus people experienced. There are some side effects — Moderna said volunteers generally tolerated their vaccine pretty well, and most problems tended to be mild to moderate. Reported problems included injection site pain (2.7 percent) after the first dose, and after the second dose, recipients reported fatigue (9.7 percent), muscle pain (8.9 percent), arthralgia (5.2 percent), headache (4.5 percent), pain (4.1 percent) and redness at the injection site (2 percent), with some overlap in these numbers among patients who experienced more than one effect. Most of these effects were short-lived. A final safety evaluation will still be needed once the trial is run to completion. While these effects are fairly mild, it's important to pay close attention to them since vaccines will ultimately have to be distributed to millions, if not billions, of people. Rare complications will be more likely to show up once lots of people get the shot. And clinical trials of other Covid-19 vaccine candidates — like the Johnson & Johnson vaccine or the University of Oxford and AstraZeneca vaccine — have already been paused due to complications among recipients. For vaccinations, safety is paramount. The Moderna vaccine has other important advantages
Monday's vaccine efficacy announcement also illustrated some critical lessons about how Moderna was able to achieve these results and other details that could influence a vaccination strategy. RNA is a viable way to make a vaccine: Moderna's vaccine is now the second RNA-based vaccine that has demonstrated a high efficacy against Covid-19. Using RNA genetic material — in this case a variant known as mRNA — is a new vaccine technology. Such an approach has never received approval for widespread use, so these results are an important validation. The way it works is that the instructions for making a piece of the virus are inserted into the body. After cells read the instructions and manufacture the component of the virus, the immune system detects it and starts to mount a response. This is a huge shift from conventional vaccines, which typically use a weakened version of the live virus, a whole dead virus, or a fragment of the virus. With RNA and similar DNA-based vaccines, there is no viral structure injected. Like the Pfizer and BioNTech vaccine, Moderna's RNA-based vaccine also codes for the spike protein of SARS-CoV-2, the virus that causes Covid-19. The spike is the part of the virus that lets it enter cells and take them over, and teaching the immune system to target this component has now been demonstrated to be a viable strategy. Moderna's vaccine appears to protect against mild and severe Covid-19: Efficacy in this context is defined as the share of vaccinated people who actually receive protection against the disease in question. For Covid-19, Food and Drug Administration guidelines say that a vaccine needs to provide protection against the coronavirus for at least 50 percent of the people who get it. That means at least half of the people who get the vaccine have to have some form of protection. At 94.5 percent efficacy, Moderna's results vault over this benchmark. But the company went a step further, reporting that out of the 11 severe Covid-19 cases it identified in its trial pool, all were in the placebo group and none in the vaccine group. What this shows is that the vaccine is effective against severe manifestations of the illness. It may be the case that someone who gets vaccinated could still get a mild infection, but it's likely the vaccine will keep them out of the hospital. While 11 is a small number of cases, it's unlikely to have occurred by chance. One lingering concern is that Moderna hasn't disclosed how long this protection will last, and it may not be able to find out without simply waiting and seeing. Figuring out the duration of protection from a vaccine will likely require long-term monitoring. Government support played a crucial role: Just about every vaccine candidate has benefited from the government's efforts to speed up trials. The FDA allowed experimenters to run phases of clinical trials concurrently and accelerated many of their regulatory approval processes. The US government has also committed to buy millions of doses of a vaccine from whichever manufacturer crosses the line under Operation Warp Speed, a US government initiative aimed at procuring 300 million Covid-19 vaccine doses by January 2021. That's a big reason a Covid-19 vaccine may be on the market in record time, likely within two years instead of the typical decades-long development that vaccines usually require. Moderna also received a direct boost under Operation Warp Speed. The Department of Health and Human Services awarded the company $483 million in April, followed by $472 million in July to support clinical trials. Then in August, HHS announced $1.5 billion in manufacturing support for Moderna's vaccine. It's easier to keep Moderna's vaccine cool than the one from Pfizer and BioNTech: Moderna was quick to highlight that its vaccine candidate has much lighter logistical requirements and can be stored at warmer temperatures than the one developed by Pfizer and BioNTech. Moderna's vaccine requires long-term storage at minus 20 degrees Celsius (minus 4 degrees Fahrenheit) and is stable for 30 days between 2 and 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit). That's well within the temperature range of conventional refrigerators. Pfizer and BioNTech's vaccine, however, demands temperatures of minus 70 degrees Celsius (minus 94 degrees Fahrenheit) or lower, which requires ultra-cold freezers and careful shipping. That means the logistics of getting Moderna's vaccine to people are much easier. However, Moderna's vaccine, like Pfizer and BioNTech's candidates, is still a two-dose vaccine, which means every recipient will have to come back after several weeks for a second injection. And that means vaccinations will require twice the number of doses as a single-dose vaccine, adding to the cost of the effort. What happens next for a Covid-19 vaccine
There are still several key steps between the results as they were announced, completing a trial, getting approval, and getting it to everyone that needs it. The trial still has to run to completion, and both vaccine candidates — from Moderna and from Pfizer and BioNTech — need more safety data before they can seek full approval. However, they may be able to apply for an Emergency Use Authorization from the FDA. That would allow the vaccine to be used in limited cases for people facing some of the highest exposures to Covid-19, like health workers and workers in essential roles. "Moderna intends to submit for an Emergency Use Authorization (EUA) with U.S. FDA in the coming weeks and expects the EUA to be based on the final analysis of 151 cases and a median follow-up of more than 2 months," according to Moderna's press release. Once a vaccine gets approved, a global supply chain, from the glass vials that hold the vaccine to the syringes used to inject them, needs to spool up to make huge quantities of the vaccine. Manufacturers will also have to ensure that vaccines remain intact and under strict temperature controls from the factory to the hospitals and clinics where they will be used. The process of manufacturing, distributing, and administering a vaccine could take months. And vaccine research doesn't end once a vaccine gets approved. Researchers and companies will still have to track complications across millions of people and pay attention to how quickly immunity wanes. It's also important to remember that a vaccine is not enough on its own to end the pandemic. Measures like social distancing, good hygiene, and wearing face masks will remain essential to control the spread of Covid-19 until a vaccine is widely available. Public acceptance will also be a major issue, and health officials will have to overcome a rising wave of vaccine hesitancy. While the end of the pandemic is now coming into focus with the latest vaccine announcements, a lot of hard work is still needed, and some of the toughest days of the Covid-19 pandemic lie ahead. | 
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