Straight to the point

I’ve been getting frequent requests for at least the last six months to write about the Novavax covid vaccine. I’ve been resisting, mainly because it’s seemed uncertain whether it would ever actually be approved in the western world. Now that it’s been approved for use in the EU, however, that has changed, and I figure that I can put it off no longer.

I guess the reason so many people are excited about the Novavax vaccine is that it uses a traditional technology that’s been used many times previously, rather than the new-fangled technologies used in the mRNA and adenovector vaccines that have up to now been all that’s available in the US and EU. To many people, that apparently makes it feel inherently safer.

The Novavax vaccine consists of two parts: the Sars-Cov-2 spike protein and an adjuvant (a substance that causes the immune system to realize that a dangerous foreign entity is present, and which thus activates an immune response to the spike protein). So, rather than injecting genetic blueprints in to the body that get cells to make the viral spike protein themselves (as is the case with the four previously approved vaccines), the spike protein is injected directly.

The first country to approve the Novavax vaccine was Indonesia, which approved it for use in November. That means that there is no even slightly long term real world follow-up data available yet. All we have is the preliminary results from the randomized trials. That means we still have no idea about rare side-effects, and won’t for months. Several million people had already received the AstraZeneca vaccine before authorities realized it could cause serious blood clotting disorders, and millions had also received the Moderna and Pfizer vaccines before it became clear that they can cause myocarditis. With that cautionary point having been made, let’s take a look at what the preliminary results from the randomized trials show.

The first trial results concerning the Novavax vaccine appeared in the New England Journal of Medicine in May. 4,387 people in South Africa were randomized to receive either the vaccine or a saline placebo. The trial was conducted during the final months of 2020, when the beta variant was dominant in South Africa. Like the earlier covid vaccine trials, the objective of the study was to understand the ability of the vaccine to prevent symptomatic disease, which was defined as symptoms suggestive of covid-19 plus a positive covid test.

The average age of the participants was 32 years and chronic conditions were rare, so this was a group at low risk of severe disease. When this fact is combined with the relatively small total number of participants (for a vaccine trial), there was no possibility that the study was going to say anything useful about the ability of the vaccine to prevent severe disease. So this was really a trial looking at the ability of the Novavax vaccine to prevent the common cold in healthy young people.

Let’s look at the results.

As with the earlier published vaccine trials, data on efficacy was only provided two months out from receipt of the vaccine. At the two month mark, 15 people in the vaccine group had developed symptomatic covid-19, as compared with 29 people in the placebo group. This gives a relative risk reduction of 49% against the beta variant at two months post vaccination, which is disappointing. It’s below the 50% risk reduction that regulators have set as the minimum level required for them to approve a vaccine.

It’s even more disappointing when you consider that efficacy against symptomatic infection likely peaks at two months out from vaccination, and then drops rapidly – that is the pattern that’s been seen with all the other approved covid vaccines, and it’s very likely that the same is true for this vaccine.

Furthermore, the beta variant is long gone. The other approved vaccines appear to have little to no ability to prevent infection from the currently dominant omicron variant (although they do still seem to reduce the risk of severe disease to a large extent). Here in Sweden you are currently just as likely to get covid regardless of whether you’ve been vaccinated or not, but you’re still far less likely to end up in an ICU due to severe covid if you’ve been vaccinated. There’s no reason to assume that this vaccine is any different.

Let’s move on and look at safety. Safety data was only provided for a sub-set of patients, and for the first 35 days out from receipt of the first vaccine dose. What little there was though, was somewhat discouraging, with twice as many adverse events requiring medical attention in the group receiving the vaccine as in the group receiving the placebo (13 vs 6), and twice as many serious adverse events in the group receiving the vaccine (2 vs 1). To be fair though, the small absolute numbers make it impossible to draw any conclusions about safety based on this limited data. So we’ll wait to pass judgement.

Let’s move on to the second trial, which was published in the New England Journal of Medicine in September. This was a much larger trial than the first, with 15,187 people in the UK who were randomized to either the Novavax vaccine or a saline placebo. Like the earlier study, it was looking at the ability of the vaccine to prevent symptomatic disease. The study ran from late 2020 to early 2021, during a time when the alpha variant was dominant, so the results of the study apply primarily to that variant. 45% of the participants had at least one risk factor that would predispose them to severe disease, and the average age was 56 years.

Ok, so what were the results?

Among participants who received two doses of the vaccine, there were 96 covid infections in the placebo group, but only 10 in the vaccine group during the three month period after receipt of the second dose. This gives an efficacy during the first few months of 90%, similar to what was found in the Moderna and Pfizer vaccine trials. One person ended up being hospitalized for covid-19 in the placebo group, while no-one was hospitalized in the vaccine group – so unfortunately there again weren’t enough hospitalizations to be able to say anything about the ability of the vaccine to prevent severe disease (although it’s pretty clear from this study that even for a relatively high risk group, the overall risk of hospitalization due to covid is low – of 96 people in the placebo group who got covid, only one required hospitalization).

Let’s turn to safety. Safety data is only provided for the period from receipt of the first dose to 28 days out from receipt of the second dose, so we don’t learn anything about the longer term, but at least for that shorter period, there was no signal of serious harm. There were 44 serious adverse events in the vaccine group, and 44 serious adverse events in the placebo group. One person in the vaccine group developed myocarditis three days after receipt of the second dose, which suggests that the Novavax vaccine might cause myocarditis, just like the Pfizer and Moderna vaccines do.

Let’s turn to the final trial, which was published in the New England Journal of Medicine in December. It was carried out in the United States and Mexico during the first half of 2021. Just as with the previous trial, the results apply primarily to the alpha variant. 29,949 participants were randomized to either the Novavax vaccine or a saline placebo. Like the other two trials, the purpose was to see if the vaccine prevented symptomatic disease, again defined as symptoms suggestive of covid-19 plus a positive PCR test. The median age of the participants was 47 years, and 52% had an underlying condition that would predispose them to more severe disease if infected with covid-19.

So, what were the results?

At 70 days out from receipt of the second dose, 0.8% of participants in the placebo group had developed covid-19, compared with only 0.1% in the vaccine group. This gives a relative risk reduction of 90%, a result that is identical to that seen in the previous trial. Unfortunately, no information is provided on hospitalizations, which I assume means that not one of the 29,949 people included in the study was hospitalized for covid-19, so, just as with the earlier trials, it’s impossible to tell if the vaccine results in any meaningful reduction in hospitalizations.

At 28 days post receipt of the seond dose, 0.9% of participants in the vaccine group had suffered a serious adverse event, compared with 1.0% of participants in the placebo group. That is encouraging.

Ok, let’s wrap up. what can we conclude about the Novavax vaccine after looking at the results of these three trials?

First, we can conclude that it effectively protected people from symptomatic covid due to the alpha variant at two-three months post vaccination (which of course tells us nothing about how effective the vaccine is after six months or a year). That information is now mostly of historical interest, since alpha is long gone and we’re living in the era of omicron. If the Novavax vaccine is similar to the four previously approved vaccines, then it’s likely useless at preventing infection due to omicron.

Second, it’s impossible to conclude from these trials whether the Novavax vaccine results in any reduction in risk of hospitalization due to covid, for the simple reason that not enough people ended up being hospitalized. Having said that, my guess would be that it probably does protect against hospitalization and need for ICU treatment, just as the other approved vaccines do. At its heart, it’s doing the same thing as they are – generating an immune response to the spike protein found on the original Wuhan covid variant, and the overall trial results are very similar to the trial results for the Moderna and Pfizer vaccines.

The overall safety data suggests that the vaccine is pretty safe, with serious adverse events being balanced between the vaccine group and the placebo group. Rare side-effects are however not detectable in randomized trials with a few tens of thousands of participants. For that longer term follow-up with much larger numbers of people is necessary. So it’s currently impossible to know whether the Novavax vaccine can cause myocarditis, like the mRNA vaccines, or blood clotting disorders, like the adenovector virus vaccines, or some other type of rare adverse event entirely. It’s therefore impossible to say at the present point in time whether it will turn out to be more safe, or less safe, or equivalent to the already approved vaccines.

[do_widget id=blog_subscription-17]

Source: Covid 19 – Sebastian Rushworth M.D. Read the original article here: https://sebastianrushworth.com