Omicron and Original Antigenic Sin

A small study of breakthrough infections provides further evidence that Omicron likely benefits from immune imprinting, or Original Antigenic Sin, in the vaccinated. The authors, mostly from UC San Francisco and UC Berkeley, conducted neutralisation assays on 144 plasma samples from 81 individuals, 63 of them double-vaccinated, and 18 of them boosted. None of the subjects had been infected prior to vaccination, but 53 suffered breakthrough infections. Thirty-nine of these breakthroughs were probably Delta, and 14 were Omicron.

The authors subjected the convalescent plasma of their vaccinated and infected subjects to live virus and virus-like particle neutralisation assays. Basically, they introduced to the plasma either Delta and Omicron viruses, or synthetic particles with key Delta or Omicron proteins, to see how well the antibodies in the plasma neutralised these variants.

The results are straightforward:

1) SARS-2 vaccination against wild-type Spike, plus Delta breakthrough infection, elicits an antibody response that is about equally effective against Delta and wild-type SARS-2. Against Omicron, however, the combination of vaccination and Delta infection is markedly less effective.

Vaccination + Delta infection neutralisation assay: The y-axis, on a log scale, gives the plasma dilutions that neutralise 50% of the live virus. Higher numbers indicate a more effective antibody response (because the plasma can neutralise the virus even when highly diluted). WT = neutralisation of wild-type SARS-2, compared on the left to neutralisation of Delta, and on the right to neutralisation of Omicron. Blue lines mark subjects who had asymptomatic or mild infections, red those who had moderate or severe infections.

2) SARS-2 vaccination against wild-type Spike, plus Omicron breakthrough infection, elicited an antibody response that was vastly more effective against Delta and wild-type SARS-2 than Omicron. Specifically, vaccinated-plus-Omicron plasma was 2.2 times more effective against wild-type SARS-2 than Delta, and 6.6 times more effective against wild-type SARS-2 than Omicron.

Vaccination + Omicron infection neutralisation assay. Omicron cases trend much milder, hence the relative scarcity of red lines (moderate or severe infections) compared to the Delta breakthroughs above.

Yes, the numbers are very small, antibodies are merely one aspect of immunity, this is very preliminary work, etc. Note also the figure that the authors don’t compute for you: Omicron breakthrough infection yielded plasma that was also three times more effective against Delta than Omicron, even though the Omicron-infected subjects had no exposure to Delta. Delta Spike is more similar to legacy wild-type Spike than Omicron, and it is wild-type legacy Spike that vaccinated immune systems target, even after breakthrough infection with the newest variant.

Note, finally, the overall lower antibody levels in the Omicron breakthrough cases. Vaccination plus Omicron gives you about one-third the neutralising activity against wild-type SARS-2, as vaccination plus Delta. As the authors note (p. 16), this is surely down to the mildness of Omicron infection. A briefer, less severe illness means reduced exposure to the virus and fewer antibodies. Your immune system isn’t going to invest heavily in fighting minor threats, and in this it much wiser than our governments and public health establishments.

It is hard to imagine a worse strategy than universal vaccination against a single, obsolete virus protein. Every booster dose just further ingrains this off-target immunity, ultimately assisting Omicron in its spread. Here we are saved only by Omicron’s starkly reduced pathogenicity. In causing mild, fleeting illness in most of those infected, Omicron spreads more effectively in virus-paranoid populations, and it provokes fewer antibodies, expanding its prospects for reinfection and continued, endemic circulation.

All of the other endemic coronaviruses that regularly infect us work in much the same way. They are pervasive, they cause very mild illness, and they commonly reinfect their hosts every 1 to 3 years. We are not on the verge of the endemic phase, we are in it. There will be seasonal SARS-2 infection spikes probably for as long as humans walk the earth. The vaccinators, unless they are stopped, will only make these spikes more dramatic and disruptive.