Vaccine trial results – how good are they? Really good.

Two vaccines – Pfizer and Moderna – have now announced the preliminary results of their Phase III trials. And it’s very good news – the results are very strong, and supported by enough data that they are almost certainly more than 90% effective (VE – vaccine efficacy), with their best estimate being 95%. That’s much more than most commentators had hoped. If 100 people without the vaccine would have come down with Covid19, only 5 of those people would come down with it post vaccination.

Pfizer’s latest press release said

• Primary efficacy analysis demonstrates BNT162b2 to be 95% effective against COVID-19 beginning 28 days after the first dose; 170 confirmed cases of COVID-19 were evaluated, with 162 observed in the placebo group versus 8 in the vaccine group
• Efficacy was consistent across age, gender, race and ethnicity demographics; observed efficacy in adults over 65 years of age was over 94%

Moderna’s press release said:

The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5% (p <0.0001).

A secondary endpoint analyzed severe cases of COVID-19 and included 11 severe cases (as defined in the study protocol) in this first interim analysis. All 11 cases occurred in the placebo group and none in the mRNA-1273 vaccinated group.

The 95 COVID-19 cases included 15 older adults (ages 65+) and 20 participants identifying as being from diverse communities (including 12 Hispanic or LatinX, 4 Black or African Americans, 3 Asian Americans and 1 multiracial).

In each case, there is so far only a press release, no peer reviewed scientific paper. The deep analysis will be by the regulators and presumably will appear in scientific papers afterwards. And in both cases, this was effectively both a Phase 2 (is the vaccine safe for a large diverse group) and Phase 3 (does the vaccine work to prevent disease, which is the subject of this post) trial.

Pfizer enrolled 43,661 participants, of whom 41,135 have had both doses of the vaccine (with 50% getting the placebo in a double blind trial – neither the participants nor the providers knew who was getting the placebo). A total of 170 of those went on to develop Covid19 disease – 162 in the placebo group and 8 in the vaccine group. There were 10 severe cases of Covid 19 – that was 9 in the placebo group and 1 in the vaccine group. Here’s the Pfizer protocol

Those equivalent numbers for Moderna are smaller, both in cases and in absolute numbers. Moderna only talked about how many participants had received all the doses – 30,000 also in a double blind trial. A total of 95 of those went on to develop Covid19 disease – 90 in the placebo group and 5 in the vaccine group. There were 11 severe cases of Covid 19 – all in the placebo group, with no severe cases in the vaccine group.

So what made them both decide they had enough information to announce? The clue is in the event protocol. Pfizer said:

Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second dose of investigational product, a target of 164 primary-endpoint cases of confirmed COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the primary series of the candidate vaccine will be sufficient to provide 90% power to conclude true VE >30% with high probability. The total number of participants enrolled in Phase 2/3 may vary depending on the incidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential early stop for efficacy or futility.

There is a lot of jargon in there, but basically the more cases of Covid19 that have occurred in total (whether placebo or vaccine), the more confident you can be of the results – of the vaccine’s efficacy rate. The key is not so much how many people have been given the vaccine (although that is important for the Phase 2 part, testing safety), but how many cases of Covid19 have occurred. And, in a development that is good for vaccine trials, but bad for the communities that the triallists live in, the trial participants caught Covid19 more quickly than the trial designers expected. For Pfizer, 0.8% of placebo participants came down with Covid19 (0.6% for Moderna) in just over three months  – reflecting the terrible infection rates in much of the world right now.

The more cases of Covid19 have occurred, the more accurate the calculation of the effectiveness of the trial. Intuitively, that makes sense. If only 10 cases had occurred – 9 in the placebo group and 1 in the vaccine group, that tells you a lot less than if 100 cases had occurred – 90 in the placebo group and 10 in the vaccine group. So the Pfizer outcomes are stronger (so far) than the Moderna outcomes, even though the overall rates are almost exactly the same.

I went down some statistical rabbit holes, which hopefully are correct, and my calculation is that for Pfizer there is a 95% chance that it is more than 91% effective, and for Moderna, a 95% chance that it is more than 89% effective. The range of outcomes is quite small with that many cases.

And what does that mean? If you receive the vaccine, then 95% effectiveness means that in a situation where you would get definitely Covid19 without a vaccine, the vaccine will stop that 95% of the time. Given Covid19 is a serious disease, a 5% chance of catching it is still not ideal.  We’ll still be being careful about this for years to come.

Another question that has not been answered by these trials is whether they will stop someone spreading the disease. We don’t know yet whether vaccines will help with population immunity. If someone is vaccinated, and doesn’t get sick with Covid19, but can still spread it asymptomatically, then you are only safe if you have been vaccinated. If the vaccine also stops you infecting others, then non vaccinated people will be protected (herd immunity) by the vaccinated people if there are enough of them (around 60-70%)

Given the two challenges of distribution (getting 100% of the population vaccinated is going to be hard in any country, particularly poorer ones) and vaccine refusal (this worldwide survey  had only 70% very or somewhat likely to take a vaccine), a vaccine that stops the spread would speed up our recovery from this pandemic by an enormous amount.

However you look at this, these vaccine results are good news, and there has been an amazing collaboration across the world to get here..

If you want more on the statistical counts behind this – here’s an analysis of the statistics of vaccine efficacy which challenged my memory of university statistics.

Links

Joe Biden, President elect of the US has appointed his chief of staff – a long term Washington staffer, Ronald Klein. Among other roles on his CV he was in charge of the US Ebola response under President Obama. Clearly a man for the times – here is an article he wrote on 30 January about the Coronavirus and the likely response from the Trump administration. Just this article alone makes me think that Klein is an excellent choice for the role. For the sake of the US, it is shame he is not starting until January 20.

Some of the world’s leading infectious-disease experts continue to serve in the administration, led by the incomparable Tony Fauci at the National Institutes of Health, and the level-headed Anne Schuchat at the CDC. These two, along with other leaders at key science agencies (and scores of men and women working for them), have decades of experience serving under presidents of both parties, and are among the world’s best at what they do….

…Yet with no one in charge at the White House, there is no authority to resolve disputes between federal agencies; no one to hold agencies accountable for the pace and intensity with which they implement the response; no one to resolve competing requests for congressional funding; and no one to draw on the resources of the security agencies of the government to help support the response…

…Five presidents—liberals and conservatives, Democrats and Republicans—have looked to Tony Fauci for advice; it is not impossible to imagine Trump being the first to angrily dismiss the counsel he offers if it does not fit with his own poor instincts. A president who calls generals “babies and cowards” will have to sit face to face with experienced global-health-security professionals, and listen. He will have to put his isolationist biases and anti-science mind-set aside, and let expertise—not his personal inclinations or the political whims of his base—guide U.S. policy. He will have to trust bureaucrats, diplomats, career staff, and agency appointees who are not on Team MAGA.

Most of my readers have probably already seen this (I think half of you sent it to me!) but this article from El Pais in Spain is a series of fantastic visualisations of what I’ve been saying for a while about the importance of ventilation and aerolisation of the virus. Here’s just one of the visualisations, but you need to watch them build to get the full effect:

And finally, an article which I coauthored (with Karen Cutter and Richard Lyon, frequent commenters here), the latest mortality statistics from Australia, showing that deaths this year in Australia are significantly lower than expected from previous years experience.

Life Glimpses

This week and last week I’ve been at a course, in a conference room, with other people. The most people I’ve been in the same room with since March. All the guidelines were followed – social distancing (which with 20 people made it difficult to hear everyone), individual food, only being served food and drink while seated. The extra stimulation of all those people for a full day made it quite hard to get to sleep each night. While zoom is intense, it is differently intense.

Since my last post, I’ve been obsessively watching the European and US Covid19 numbers get worse and worse. It has been hard to watch as here in the Southern Hemisphere it is looking increasingly good (despite this week’s lockdown in South Australia). I’ve been thinking of everyone I know in countries which are locking down again, or should be. I don’t have the same anxiety for myself and my friends and family here in Australia that I did in March. But it continues to be a scary time for the world as a whole.

Bit of beauty

This is the season for Jacarandas in Sydney. I’ve got a selection of the most beautiful jacarandas I’ve seen this season, including the famous street in Kirribilli that still was full of instagrammers when I visited, despite the closed borders to overseas tourists.