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The Latest 5 Covid Vaccines to Pass the Phase 3 Results Milestone

Cartoon of Covid vaccines wanting to be first or second generation

By the middle of last year, 16 Covid vaccines had passed the critical milestone of announcing results from a phase 3 trial. The world still has a drastic shortage of vaccines, though – and the number of doses needed for strong protection has risen to at least 3 in the short term. Many rich countries are awash with them, but 90% of people in low income countries and nearly half in lower middle income countries haven’t had any dose (via Our World in Data).

An extra 5 vaccines have since joined the club, including a vaccine critical to the COVAX supply: the Clover vaccine is signed up with over 400 million doses. All are vaccines that don’t require super-freezing, and all but one are an “old school” type, protein subunit vaccine. And there are a couple of firsts: the first Covid vaccine using plants as the basis for production, and the first patent-free Covid vax.

Here’s an update on the trial results for this new handful of vaccines.

Soberana Plus – an add-on dose to Soberana 2

Soberana Plus is a protein subunit vaccine developed by Cuba’s Finlay Institute of Vaccines (IFV) (technical name, Finlay-Fr-1A). There were early stage trials of its use alone in people who had never been infected with SARS-CoV-2 and in people who tested positive for previous infection. Until the recent phase 3 trial result announcement, we had seen the results of a phase 1 trial in people who had been previously infected.

In July 2021, Soberana Plus joined the phase 3 trial results club, as the third dose in a 3-dose course, following 2 shots of Soberana 2. Soberana 2 is a protein subunit vaccine, too – a conjugate vaccine, where the SARS-CoV-2 component is joined with tetanus toxoid to increase its potency. A preprint for the results of this mixed vaccine schedule was posted in November.

There were 44,031 participants in this trial, aged 18-80 with 59% white, randomized into 3 groups: 2 doses of Soberana 2, the same 2 doses with a third dose of Soberana Plus, and a placebo group. That means we still don’t have efficacy results for Soberana Plus alone. Delta was taking over in Cuba as the trial progressed.

Vaccine efficacy against symptomatic Covid-19:

  • For 2 doses (without Soberana Plus): 71.0% (CI 59–79)
  • For 3 doses (with Soberana Plus): g92.4% (CI 87–96) (15 people sick in the vax group vs 155 in placebo)

Vaccine efficacy against severe Covid-19 – here the numbers are very small, so the uncertainty is very high:

  • For 2 doses: 63.0% (2 people in the vax group vs 6 in placebo)
  • For 3 doses (with Soberana plus): no one in this group developed severe Covid

There were 8 Covid deaths in the placebo versus 3 in the 2-dose group and no one in the Soberana 2 + Soberana Plus group.

There wasn’t enough data provided on adverse events, but the overall rate of solicited systemic adverse events appears to be very low, and similar to the rate in the placebo group. The rate of moderate systemic events was 7% after the first dose and 9% after the second. For grade 3 (severe), the rate was less than 1% after each of the first 2 doses. The rate after the third isn’t reported, but where they do provide data on the third dose, it was consistently lower than the first 2. (It’s not clear how common mild systemic adverse events were.) There was no increase in serious adverse events in either vaccination group. (If you want to know more about what these terms mean, check out my explainer post on safety and adverse events in clinical trials.)

In October, the outcome of the phase 3 trial of the Soberana combo in Iran was reported (including on the Finlay Institute’s blog), but detailed data hasn’t been released yet. Vaccine efficacy in that trial was reported as 91.7% (CI 21-99).

Records for this vaccine in my collection: explanatory notes for the collection here.

This vaccine is non-profit within Cuba, and so it’s discussed here in my previous post on non-profit Covid vaccines.

Zifivax – China’s first protein subunit Covid vax (ZF2001)

Zifivax is another protein subunit vaccine, developed by the Chinese Academy of Medical Sciences with its manufacturer, Anhui Zhifei Longcom. This vaccine has a lot of studies underway, from babies up. In August, the manufacturer reported brief results, and that the phase 3 placebo-controlled trial had 28,500 adult participants in China, Ecuador, Indonesia, Pakistan, and Uzbekistan.

The results of this trial still haven’t been reported. The manufacturer’s website says vaccine efficacy is 81.8% against any symptomatic Covid-19, and 77.5% against disease caused by Delta.

The results of the phase 1 and 2 trials are published, as well as a study showing it’s an effective booster for Sinopharm’s Beijing vaccine (an inactivated vaccine).

Records for this vaccine in my collection: explanatory notes for the collection here.

Clover’s SCB-2019 – another protein subunit vaccine

This is another protein subunit vaccine, and as already mentioned, a critical vaccine in for COVAX provision globally. Clover is a Chinese company with an Australian subsidiary, and the early clinical research was done in Australia. The company announced its phase 3 outcome in late September, and they published their results in January.

The efficacy trial is called SPECTRA. It’s a phase 2/3 trial, with 30,174 participants randomized to 2 doses of the vaccine or placebo, in 5 countries: Belgium, Brazil, Colombia, Philippines, and South Africa. It was expanded to include adolescents, but results are only available for adults now (up to 86 years of age).

That mix of countries has resulted in one of the most diverse populations of any of the Covid vaccine trials: around 20% are indigenous people, roughly half are Latino or Hispanic, more than a third are Asian, and around 10% are black.

All cases of Covid-19 in this trial were variants, which means you really can’t compare its results to the early vaccine trials. The Delta takeover was growing during this trial. The vast majority of Covid-19 was in trial participants in Colombia and the Philippines. The graph below from Clover shows what was happening with variants:

Vaccine efficacy in this trial (in people who had no previous infection – the usual main outcome in these trials):

  • Against symptomatic Covid-19: 67·2% (CI 54–77)
  • Against moderate to severe Covid-19: 83·7% (97·86% CI* 55·9–95·4)
  • Against severe Covid-19: 100% (CI* 25-100)
  • Against Delta (for any symptomatic disease): 78·7% (CI 57-90)
  • There were no Covid deaths in the vaccinated group (and 3 in the placebo group)

* The confidence intervals (CI) here are more demanding than usual – set at a 97.86% level. There’s an explanation of these terms below this post.

The rate of systemic adverse events reported was lower after the second dose. After the first dose, it was 36% in the vaccinated group and 34% in the placebo group. The rate of serious adverse events was low and the same between the groups, but 4 were judged to be vaccine-related (there’s not enough explanation of these, so hopefully we get that from regulators’ reports).

Records for this vaccine in my collection: explanatory notes for the collection here.

Medicago – a plant-based vaccine from Canada

The Medicago vaccine is a virus-like particles vaccine (particles that mimic the virus), using plants that can be infected by the virus for production. (The manufacturer describes their plant-based technology here.) The plant is a nicotine plant, and the company is Canadian, and part-owned by tobacco company, Philip Morris.

Medicago announced the results of their phase 3 trial in December, followed soon after by a preprint in January. There were 24,141 people randomized to the vaccine or placebo (90% white), in Argentina, Brazil, Canada, Mexico, UK, and USA – 83% had both doses of the vaccine at the time of these results.

Vaccine efficacy:

  • Against symptomatic Covid: 71.0% (CI 59-80)
  • Against Delta: 75.3% (CI 75-96)
  • Against moderate Covid: 76.6% (CI 51-90)
  • Against moderate/severe Covid: 78% (CI 54-91)
  • No one in the vaccinated group developed severe Covid vs 2 in placebo

The rate of systemic adverse events was relatively high, and higher after the second dose: 87% of people reported at least one symptom compared to 65% in the placebo group – the events in the placebo group were largely minor. The events were mild or moderate for half the vaccinated people. No serious adverse events were judged to be vaccine-related.

Records for this vaccine in my collection: explanatory notes for the collection here.

Corbevax – the first patent-free Covid vax to get an authorization

This is a protein subunit vaccine developed in Texas, and now manufactured and authorized for use in India by Biological E. It’s the cheapest Covid vaccine globally – less than half the cost of the AstraZeneca vaccine, for example, and that’s already far cheaper than the rest. Because it was developed with that goal, there is no patent, and I have discussed it in my previous post on non-profit Covid vaccines.

It’s also really unusual for another reason. Unlike almost of the vaccines at the time of authorization, we really have no idea how effective the vaccine is. Here’s how I summarized it in my previous post: Neither the manufacturers nor Indian drug regulators have released any data on the efficacy of Corbevax, and none on any phase clinical trial. Biological E’s press release reports that the trial achieved better levels of neutralizing antibodies than Covishield (the Indian-produced AZ vaccine). Because only measures of immune response were tested, even when the clinical trial data is reported we won’t really know how effective the vaccine is until it’s rolled out and effectiveness studies are done.

Biological E registered 2 phase trials, with one in adults (aged up to 80) and one in children and adolescents (from age 5). It’s the one in adults that’s just been authorized. The trial register entry for it reports that 2,140 participants were planned.

Records for this vaccine (in different formulations) in my collection: explanatory notes for the collection here.

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Cartoon of facing off coronavirus

All my Absolutely Maybe Covid-19 vaccine posts

All previous Covid-19 posts at Absolutely Maybe

My posts at The Atlanticat WIRED, and debunking posts at my personal website.

Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as my son is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.

The cartoon is my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.)

Key terms used in this post

  • Homologous vaccine schedules have the same vaccine for each dose. When the doses aren’t all of the same vaccine, that’s called heterologous – what I’m calling “mixed” in this post. The first shot in a multi-dose vaccine schedule is called the prime: doses thereafter are boosts.
  • Vaccine efficacy is a rate of risk reduction in symptomatic Covid-19 unless otherwise specified. Vaccine efficacy of 80% or 90% means if a vaccinated person is exposed to the virus, their risk of getting the disease is lowered by that proportion, so it depends on how high their risk of being exposed, and that varies. It’s not an absolute drop in percentage points. (Efficacy is for results on disease outcomes from phase 3 clinical trials; effectiveness studies follow that.)
  • When available, a range of statistical certainty for efficacy is shown, eg 92% (CI: 88-95). The distance between 88% and 95% in this example is small: it means there is a lot of certainty that 92% is about what we can expect. However, the wider that range is, the more uncertain we are.
  • The rate of efficacy set for whether a Covid vaccine works well enough is 50% (with a CI starting at 30% at least).
  • And I have a post explaining the terms used, and assessment processes, for adverse events and safety in these trials – including the difference between “severe” and “serious”.

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