Issue #109: Vaccination plus post-exposure vaccination as a treatment for Long COVID

Written by Nobel Laureate Professor Peter Doherty

Over the past few weeks (#105-108) we’ve discussed big studies showing the unsurprising reality that, with progressive changes in the SAR-CoV-2 spike protein leading to the successive global spread of different variants (alpha, delta, Omicron), the protective effect of vaccination has fallen-off.

Indeed, we all know from our day-to-day lives that many fully vaccinated people are being infected with the Omicron BA.1 and BA.2 strains, and we’re waiting to see whether further mutants (like BA.4 and BA.4) will sweep through the community (#93, #96). Though this was not obvious for earlier strains, the Omicron variants look like immune-escape variants (#64) that have mutated in previously infected and/or vaccinated people to do an ‘end run’ around the circulating neutralizing antibodies (#82) that block the binding of the SARS-CoV-2 spike to the ACE2 protein on the surface of our cells.

Despite that progressive fall-off in protection against first infection, both published data (#105-108) and clinical colleagues who deal with hospital cases emphasize that vaccination is protective against severe disease in all but the very frail elderly (and some with major co-morbidities). For those in that category, it’s very important that they gain immediate access to one of the new anti-CoV drugs (Paxlovid, or Molnupiravir) that, optimally, need to be given over the first 5 days after infection. Overall, given the very high case numbers we’ve been seeing recently, a small minority end up in hospital, and even fewer require an ICU stay.

Somewhat surprisingly to immunologists like me, the third and fourth vaccine doses are bringing up antibodies that can neutralize the Omicron variant. It’s currently unclear   whether these confer the main protection against very severe disease, or that’s due to the ‘recall’ (from memory) of killer T cells specific for unchanged components of the spike protein. The advice from the medical infectious disease community is, though, unequivocal: get your third or fourth vaccine shot as soon as it is available to you.

A different question that has been asked is: for those who are vaccinated after developing COVID-19, is there an improvement in Long COVID (LC) symptoms (#107)? The results of a large pre-Omicron study (3 February to 5 September 2021) UK NHS/ONS (#105) that looked at post-exposure vaccination for the 18-69 age range was published very recently. From a total of 323,685 participants, 28,356 had a laboratory-confirmed diagnosis of COVID-19. The mean age at the end of this study was 46 years, 56% were women and 88.7% were of ‘white ethnicity’. All had received one of two doses of either the adenovirus-vectored AstraZeneca (AZ) vaccine, or an mRNA vaccine, and they were followed for a median period of 141 days after the first vaccine dose or 67 days after the second.

Based primarily on self-assessment, the 23.7% classified as being in the LC set showed at least one continuing LC symptom during the 12 weeks after laboratory-confirmed infection. A first vaccine dose was associated with a 12.8% decrease in the odds of LC, with an additional 9.1% after the second dose followed by a further 0.8% each additional week until the end of the study.

The broad conclusion was that giving one, or better two, doses of vaccine to those who were already showing symptoms of LC tended to be associated with a beneficial decrease in activity-limiting symptoms. The study’s summary statement was: “vaccination of people previously infected may be associated with a reduction in the burden of LC on population health, at least in the first few months after vaccination.”

This was a broad-based population analysis, but there are other, smaller studies suggesting that, in the main, there can indeed be some benefit in vaccinating people who are suffering LC symptoms. However, there are also reports that vaccination can occasionally exacerbate their clinical impairment.  Summarizing the information available in January 2022, a UK Health Security Agency review concluded that the majority of people with LC either felt better or had unchanged symptoms after vaccination, though a few (perhaps 10-15%) felt worse.

But there’s a big problem with all such analyses, and that relates to the chaotic nature of the definition of LC cases. If, for example, we look at the big US VA study discussed last week (#108), it’s obvious that LC symptoms were (on average) worse for those who required hospitalization and worse again for those who survived ICU care. Basically, this manifestation of LC may well reflect permanent organ damage that, while there may be compensatory changes with time, will not allow complete recovery and is unlikely to be ameliorated by post-exposure vaccination. Even so, in order to minimize the consequences of a breakthrough SARS-CoV-2 infection with a variant strain, such individuals should receive their third or fourth vaccine dose.

What’s obviously needed though, is a comprehensive analysis of post -exposure vaccination focused on those who develop LC after a mild initial course, with a separate cohort for those who suffer reasonably bad symptoms initially but who do not require ward care. Perhaps some research group is doing this analysis, but I’ve not yet seen any results.