The long wait for results from the US phase 3 trial of Novavax’s Covid-19 vaccine had prompted worries that maybe the data were not quite up to scratch. In fact the top-line efficacy figures released today are highly respectable, with NVX-CoV2373 demonstrating overall efficacy of 90.4% and complete prevention of hospitalisation and death.
The vaccine’s efficacy did dip a little versus variants of concern or interest, which include the alpha and delta Covid-19 strains. Perhaps the bigger worry for Novavax, however, concerns the shot’s likely niche: in the US it would surely be largely relegated to the booster setting. Maybe Novavax’s plans are international in scope – but the company needs to ramp up its manufacturing capacity, and fast.
First, the good news. The 29,960-stong Prevent-19 study met its endpoint with 90.4% prevention of infection and 100% protection against moderate and severe disease. Six hospitalisations and one death occurred in the control arm, but were not included in the efficacy analysis because PCR samples were not evaluated in the central lab, as called for in Prevent-19’s protocol.
|Prevent-19: US phase 3 trial of Novaxax's NVX-CoV2373|
|Cases in high-risk populations*||13||62||75||91|
|Cases known to be:|
|Variant of concern||35|
|Variant of interest||9|
|VOC or VOI||6||38||44||93|
|Not VOC or VOI||0||10||10||100|
|Cases where variant is unknown||8||15||23||approx 75|
|*Over age 65, under age 65 with certain comorbidities, or having life circumstances with frequent Covid-19 exposure. Source: Company release, Evercore ISI.|
The jab was 100% effective in preventing Covid-19 caused by strains of the virus not considered variants of concern (VOC) or interest (VOI). Among the VOC/VOI infections, efficacy fell to 93.2%. Novavax used the US CDC’s definitions of these terms, which differ from the WHO’s.
Sequence data were available for 54 of the 77 Covid-19 cases in Prevent-19. Of these, 35 (65%) were VOC, 28 of which were caused by the alpha strain that first emerged in the UK, and which became the predominant strain in the US during the period in which the trial was conducted. Nine cases (17%) were VOI, with one of these caused by B.1.617, related to the highly transmissible delta variant, which is itself designated B.1.617.2.
|The variants of concern and interest in Prevent-19|
|WHO label||Pango lineage||Earliest documented samples||No of cases in Prevent-19|
|Variants of concern|
|Alpha||B.1.1.7||UK, Sep 2020||28|
|Epsilon||B.1.429||US, Mar 2020||3|
|Beta||B.1.351||South Africa, May 2020||2|
|Gamma||P.1||Brazil, Nov 2020||2|
|Variants of interest|
|Iota||B.1.526||US, Nov 2020||6|
|Zeta||P.2||Brazil, Apr 2020||1|
|No Greek name||B.1.526.1||US, Oct 2020||1|
|No Greek name - related to delta variant||B.1.617||India, Feb 2021||1|
|Source: Novavax presentation, CDC.|
This leaves 23 cases, eight of which were in the vaccine arm, that were caused by variants unknown. According to Umer Raffat of Evercore ISI, the vaccine’s efficacy among these 23 cases was around 75% – much lower than in the other groups.
On a conference call today Novavax said that not enough viral RNA was recovered from these samples to allow sequencing, and pointed out that the eight cases in the vaccine arm caused by unknown variants were all mild disease, as might be expected if little virus was present.
Asked whether these cases might have included the delta variant, the company said that this was “really speculative”, but added that it was looking at other approaches to sequencing to try to nail down which variants were present in the group. Any such findings will be presented in a future post-hoc analysis.
Now to the troublesome part. Novavax intends to file for regulatory authorisations in the US, EU and UK in the third quarter; it has already started an emergency authorisation application in the US, and completion of this might allow it onto the market without having to get a BLA as the FDA has recently stipulated for Covid-19 vaccines.
Before that it will have to complete the process qualification and assay validation needed to meet chemistry, manufacturing and controls requirements to resolve earlier manufacturing delays (Covid-19 vaccine leaders make hay while Novavax flounders, May 11, 2021).
By the time the vaccine reaches market in the US and UK, of course, there will be precious few people who need it. On the call today management more or less admitted that in the US, in 2022, the market would transition into requiring boosters. It said it had not yet looked at pricing in this setting.
The company reckons it can manufacture 150 million doses per month by the end of the fourth quarter of 2021. For comparison, Pfizer and Biontech expect to deliver 2.5 billion doses during 2021.