Why wouldn't the Pfizer, Moderna, AstraZeneca, and Johnson & Johnson vaccines be equally effective?

Question

Based on what I have read, the Pfizer, Moderna, AstraZeneca, and Johnson & Johnson COVID-19 vaccines all work by training the immune system to recognize the spike protein on the surface of the SARS-CoV-2 virus.

I understand that the vaccines deliver the genetic instructions for creating the spike protein in different ways - the Pfizer and Moderna vaccines use mRNA, while the AstraZeneca and Johnson & Johnson vaccines use an adenovirus.

But if the end result is the same - a person's immune system being able to recognize the same spike protein no matter which of the 4 vaccines was administered, then shouldn't the vaccines be equally effective? I assume they are not though - why is that?

(It has been reported in Live Science and The Atlantic that the vaccines each have a different efficacy - 95% for Pfizer, 94% for Moderna, 70% for AstraZeneca, and 66% for Johnson & Johnson - but those efficacy numbers cannot be compared since they are based on trials conducted during different stages of the pandemic with different people in different regions.)

Answer 1

Even assuming the same ecological conditions, efficacy of a vaccine is in a (dose-dependent trade-off with side effects. (This was e.g. easily shown in the phase I/II trials of Moderna's vaccine.) Even for the exact same tech/vaccine, manufacturers may choose different points along this curve.

Furthermore, the amount of "training" and thus resulting levels of antibodies etc. depends on how long the injected vaccine lasts in your body. There are numerous factors that affect this, see e.g. prior discussion here what affects that in mRNA vaccines alone.

Changing the delivery vector to something more substantially different, e.g. from a lipid nanoparticle (LNP) to an adenovirus (Janssen, Astra-Zeneca, Sputnik) can have more substantial effects in both of the above regards; i.e. the side-effect vs efficacy profile may be on different curve; the technology that makes a pure mRNA vaccine persist long enough in your body is not the same as that using an adenovirus--by the way, the latter is a DNA virus, so the protein is coded in a slightly different substrate, with a different "decay rate". You can also have prior immunity to some adenoviruses (and also develop it from the vaccine, I think).

Furthermore, some other Covid-19 vaccines (e.g. Novavax) deliver the proteins themselves (in a LNP) rather then mRNA, so they are even more fundamentally different than mRNA/DNA based ones with respect to all of the above. The same mRNA molecule can get reused a good number times in a cell to produce (spike, in this case) proteins, but a protein is more or less of "one use" for the immune system. Generally speaking, protein vaccines (and this include's Novavax) use various adjuvants to get more immune response out of the same dose of proteins, which are fairly involved to manufacture. (Such adjuvants aren't used by current mRNA vaccines that have been approved, probably because they generate [translate to] more than enough proteins.)

Of the vaccines you've listed, Pfizer/Biontech and Moderna are the most similar to each other technology-wise (both mRNA in a PEGylated LNP--their actual formulation differences are somewhat obscure), so somewhat not surprisingly they produced the most similar results.

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Additionally, small changes have been made to the genetic sequence of the spike protein; more specifically

• Astra-Zeneca & Sputnik don't report any modifications
• Pfizer and Moderna (both) made the same proline substitutions
• Janssen additionally made two mutations at furin cleavage sites
• Novavax made three of those

The role of proline substitutions is to keep the (produced) spike protein in the prefusion conformation for a longer time, thus effectively increasing yield. If you wonder how they both got this idea: it's because this was first done on a MERS vaccine. It was observed that most of the naturally produced antibodies target the RBD, which is only exposed in the prefusion conformation.

According to Janssen's pre-clinical research, their furin mutations have an additional stabilizing effect and cause the host to produce a greater ratio of neutralizing to non-neutralizing antibodies (compared to the variant with the two proline substitutions only). Novavax basiscally did the same thing but altered the cleavage site at three points RRAR→QQAQ.

Answer 2

As Fizz noted in a comment, from what we know about the vaccines, the Novavax and Janssen vaccines make slightly different modifications to the spike protein than the Moderna and Pfizer vaccines. In other words, they are not delivering the exact same instructions for recognizing the virus.

We don't know if these small differences are what causes the difference in efficacy. But your assumption that the "end result" is the same is not necessarily valid. There may be differences in the nature or degree of the immune system's ability to recognize the virus because, in a manner of speaking, the different vaccines give slightly different instructions for doing so.

It's also worth noting that the different vaccines were tested at different times and in different places. It's possible that differences in their measured efficacy reflect different COVID-19 variants that were prevalent in the populations where the trials took place.