Preliminary testing data for CureVac’s anti-covid vaccine, the cheapest and easiest-to-store mRNA preparation hoped to be distributed worldwide, did not yield the desired results. CureVac’s vaccine appears to be just 47% effective against CoViD-19, a value below the minimum threshold set by the WHO, which could jeopardize its approval. What went wrong? And why are Pfizer and Moderna vaccines, also mRNA-based, instead of extremely high efficacy?
Variants effect? According to CureVac, the German pharmaceutical company that produced the vaccine, it could in part depend on the coronavirus variants widespread in the ten countries between Europe and Latin America in which the phase 3 studies took place (among these there is the little known Lambda variant, first identified in Peru). Only one case, among the 124 covid infections that occurred during the trial for which a genetic sequence was obtained, is in fact attributable to the original strain of SARS-CoV-2.
Still, other mRNA vaccines offer high coverage even against variants. Pfizer’s has an efficacy of 92% against infections from the Alpha variant (or English, in the old wording), 83% against the Delta variant (initially identified in India) and 75% against the Beta variant (emerged in South Africa). In short, it’s all the fault of the variants.
A difficult balance. Based on the first hypotheses, summarized in an article published on Nature, the problem would rather concern the vaccine itself, in particular the relationship between dosage and composition. During phase 1 tests, those in which the optimal dosage is decided, the scientists of the University Hospital of Tübingen (Germany) had evaluated a dosage between 2 and 20 micrograms of mRNA for each injection. In the higher dose, however, the CureVac vaccine caused too many adverse effects, such as severe headaches, chills and fatigue. It was therefore decided to lower the dosage.
At 12 micrograms, the vaccine appeared to be well tolerated and all subjects developed antibodies. However, the levels of neutralizing antibodies were relatively low, similar to those found in those recovered from natural infection, but much lower than those found in vaccinated with Pfizer or Moderna, which in fact require higher mRNA dosages. According to experts, this should already have been a first wake-up call for subsequent outcomes. But the point is: why can’t the CureVac vaccine be given in more massive doses like the others, without causing major side effects?
Changes needed? If we stop to analyze the composition of the vaccine, the answer could be either in the lipid (i.e. fat) molecules used to protect the mRNA, or in the same genetic instructions for the spike protein delivered to our cells. The lipid blisters that the CureVac vaccine is wrapped in are nearly identical to those used for Pfizer and Moderna.
All mRNA vaccines give the body instructions to code for the spike protein, which SARS-CoV-2 uses to access cells in the human body. The cells thus instructed produce the spike for a short time, in the absence of infection, so that the immune system learns to recognize it and block it in case of subsequent contacts.
However, Pfizer and Moderna’s vaccines use mRNA modified. One of the bricks is changed (nucleosidi) that make up its molecule – in this case, uridine is replaced with pseudouridine – in order to inhibit the immune reaction of the human body and get the mRNA directly to the cells: otherwise, the genetic instructions entered would be immediately recognized as strangers. This step is thought to circumvent the more pronounced inflammatory reactions put in place by the body.
The CureVac vaccine instead alters the RNA letter sequence to try to do its job without being blocked by the immune defenses. Advocates of modified mRNA technology have long argued that this is the secret to the high efficacy of these next-generation vaccines. And the CureVac vaccine problems may prove them right.
Waiting for answers. There are other possible explanations that are not yet discarded: structural differences in regions that do not code for the spike in the genetic instruction string; or precisely the higher storage temperature, which may have accelerated the degradation of mRNA. The answers we find will be important not only for the anti-covid vaccines, but also for the mRNA technology itself, and for the treatment prospects it offers. Meanwhile, CureVac is working, together with London-based pharmaceutical company GlaxoSmithKline, on another unmodified mRNA-based anti-covid vaccine that has resulted in ten times higher production of neutralizing antibodies in animals.