It is almost incomprehensible that Novavax has succeeded with a Covid-19 vaccine while some global vaccine giants have stumbled, or even outright failed. And data suggest that the tiny developer's NVX-CoV2373 has convincingly kept up with – and in some cases outmanoeuvred – larger rivals.
Almost 90% efficacy was achieved in the company’s pivotal UK trial; disappointingly, the so-called South Africa variant of the virus substantially reduced the jab’s effectiveness in a separate trial. A win for Johnson & Johnson’s single-shot approach swiftly followed Novavax’s news, with what could be construed as weaker efficacy that also struggled to hold up against concerning mutations.
These two new datasets suggest that the path out of this pandemic will be longer than many hoped. True, all the successful vaccines seem capable of reducing the incidence of severe disease, which can certainly be considered a win. But the Novavax and J&J data show that highly mutated variants are more able to evade these jabs, and that previous infection with the original strain provides little protection.
Vaccine development against Covid-19 is far from over with these first-wave injections. Both Novavax and J&J made clear that work on next-generation versions was under way; the former plans to move new candidates into the clinic in the second quarter. Data from Novavax’s trial conducted in South Africa show why such products could be necessary.
|UK trial (n=15,000)||S Africa trial (n=4,400)|
|Primary efficacy endpoint||89.3%||49.4% (60.0% in HIV negative)|
|Efficacy against original Covid-19 strain||95.6%*||~95%|
|Efficacy against local variant||85.6%*||~55% (in HIV negative)|
|*Calculated post-hoc by Novavax **SVB Leerink estimates. Source: company statement, analyst note.|
The B1351 variant, first identified in South Africa, is one of the most concerning to have emerged because it carries certain mutations thought to confer some resistance to antibodies. The Novavax data seem to confirm this, with topline efficacy dropping to 60.0% in HIV-negative patients in the smaller phase IIb trial conducted in that country, compared with 89.3% achieved in the large pivotal UK trial.
B1351 has spread widely throughout South Africa, and Novavax found that the variant was responsible for almost all of the Covid-19 infections in the study.
Around a third of participants had antibodies indicating prior infection when they entered the South Africa study, and these were likely to have been caused by the original viral strain, Novavax said. Among placebo patients the attack rate was largely the same in antibody-naive and positive cohorts, with subsequent infections largely caused by the variant.
“These data suggest that prior infection with Covid-19 may not completely protect against subsequent infection by the
More gloomy conclusions can be drawn here, specifically with regards to hopes that herd immunity, via natural immunity and the first wave of vaccines, will be achieved any time soon. Leerink analysts painted a starker picture, predicting that resistant variants would likely spread rapidly through the US and other countries, and that “vaccination and prior infection will only contribute to selection pressure in favour of the new variant”.
|J&J: Ensemble results (n=43,783)|
|Primary efficacy endpoint at 28 days||66%|
|Protection in the US||72%|
|Protection in Latin America||66%|
|Protection in South Africa||57%|
|Source: company statement.|
Data from J&J also seem to echo this message, with the company’s single-dose vaccine Ad26.COV2.S/JNJ-78436735 providing a remarkably similar level of protection against moderate or severe disease in South Africa, in the phase III Ensemble trial. Direct comparison of these results is far from robust, of course, and comes with the usual caveats. But it seems fairly clear that Ad26.COV2.S is also less effective against the more highly mutated variant.
Whether these new variants cause more severe disease remains a subject of debate, as is the extent to which it will render existing vaccines less useful. But at the very least these two datasets underline the need for this first wave of vaccines to be as potent as possible, to really make a mark on the pandemic.
Apples to apples?
Making a case for potency is where J&J faces a battle, with the headline 66% efficacy figure in Ensemble numerically lower than Novavax’s results, and the readouts generated earlier by Pfizer and Moderna. Caveats apply, of course; Mattaus Mathai Mammen, head of R&D for J&J, said comparing topline efficacy readouts across pivotal vaccine programmes conducted at different times in the pandemic was particularly unsound.
“The pandemic has changed. There are now a large number of variants around, some are more virulent, and some are better at circumvention. So you cannot compare our 72% in the US to the 95% achieved at another time,” he said.
This might well be true, although it will not stop such comparisons. Which is probably why J&J chose to focus heavily on another number: the 85% reduction in severe disease across the trial, with the jab demonstrating 100% protection against hospitalisations and death.
It should also be remembered that J&J achieved these results with one dose of Ad26.COV2.S, a fact that will help the company make convincing arguments around logistics.
Still, with safety seemingly a non-issue for both vaccines, Novavax and J&J look to be on their way to market. And while this is far from the end of the journey for Covid-19 vaccine development, a week that started with the exit of Merck & Co has at least ended with two wins.