Scientists say that understanding whether vaccines help some long Covid patients but not others could help unravel the underlying causes of different symptoms and potential ways to treat them.
“They might be different disease processes and you manage them differently,” said Dr. Adam Lauring, a virologist and infectious disease physician at the University of Michigan. “It might be that there’s a subset of people who have a certain type of long Covid, who respond well to vaccines, but there might be other people who have a different subtype that we haven’t quite defined yet.”
Akiko Iwasaki, an immunologist at Yale, said that a vaccine, by generating antibodies to the coronavirus’s spike protein, could potentially eliminate vestiges of the virus or remnants of viral RNA that may linger in some patients.
If this is occurring, she said, it could suggest that the vaccine “might be like a permanent cure” for those patients.
Dr. Iwasaki said the vaccine might also help people whose long Covid symptoms may be caused by a post-viral response resembling an autoimmune disease if “the vaccine stimulates innate immune responses that dampen these kinds of autoreactive responses,” she said. But based on experiences of people with other autoimmune diseases, that relief would “not be very long-lasting and they would kind of revert back” to having symptoms like fatigue, she said.
Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Institute in San Diego, said he is starting a study to measure physiological information like heart rate, respiratory rate, temperature and markers of immune system response in people with long Covid before they receive a vaccine and weeks afterward.
It’s plausible that “you have your immune system revved up when you’re fighting a reservoir” of virus or RNA remnants, he said, “and that could be an explanation of why you’re in overdrive with your heart rate.” He wants to see if these biological indicators improve post-vaccine.
“We’d really like objective metrics that show that you not just feel better,” Dr. Topol said. “You could feel better from the placebo effect, but it’s unlikely your heart rate’s going to go from 100 to 60 because of a placebo effect. And if we keep seeing that pattern, that would be like Eureka.”
He added, “I think there’s probably something there, but I just don’t know what is the magnitude, how many people are going to benefit.”
There are many other questions: Are there specific characteristics, like age, gender, type or duration of symptoms, that might make some long Covid patients more likely to feel better? Would a vaccine be less effective for people with more complex conditions: people whose symptoms are driven by multiple biological pathways (perhaps both an RNA remnant and autoimmune activation) or whose symptoms have changed or fluctuated over time? Are certain types of vaccines more likely to produce benefit?
- Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine – NEJM
- Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. – medRxiv
- COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection– medRxiv
- Are vaccines safe in patients with Long COVID? A prospective observational study – medRxiv
- Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study – The Lancet – Eric Topol
- Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers” – Wiley
- How Vaccines Might Improve Long Covid A working hypothesis from an expert immunologist – Iwasaki
- NIH launches new initiative to study “Long COVID” – NIH
- Long-term Impact of Infection With Novel Coronavirus (COVID-19) – UCSF
- LIINC Study on Long COVID – UCSF
- Long-term Impact of Infection With Novel Coronavirus (COVID-19) (LIINC) – NCT04362150
- First manifestation of adult-onset Still’s disease after COVID-19 – The Lancet – Eric Topol
- Post-acute COVID-19 syndrome – Review, Nature Medicine – Eric Topol
- Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers” – Wiley
- Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2 – Nature Medicine
- Antibodies elicited by SARS-CoV-2 infection and boosted by vaccination neutralize an emerging variant and SARS-CoV-1 – medRxiv
- 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records – The Lancet
- Some long-haul covid-19 patients say their symptoms are subsiding after getting vaccines – Washington Post
- Long Covid Is Not Rare. It’s a Health Crisis. – NYT
- They Had Mild Covid. Then Their Serious Symptoms Kicked In. – NYT
- Many ‘Long Covid’ Patients Had No Symptoms From Their Initial Infection – NYT
- Do Vaccines Help COVID Long-Haulers? – MedPageToday
- Long Covid symptoms ease after vaccine, say sufferers – The Telegraph
- Dr David Strain, a clinical senior lecturer at the University of Exeter who runs long Covid clinics and is a member of the NHS taskforce on Long COVID
- Professor Danny Altmann, an immunologist at Imperial College London
- Professor Eleanor Riley, immunologist at the University of Edinburgh
- Charles Bangham, Chair in immunology at Imperial College London
Patient Support Groups:
- The Patient-Led Research Collaborative for Long COVID
- COVIPS-19 Support Group – Body Politic
- Survivor Corps
- NHS to offer ‘long covid’ sufferers help at specialist centres – NHS
- Member briefing: Understanding long COVID – NHS Confederation
- Post-COVID Syndrome (Long COVID) – NHS
- Supporting your recovery after COVID-19 – NHS
- Updated estimates of the prevalence [300,000] of long COVID symptoms – ONS
- Press release. £18.5 million to tackle long COVID through research – GOV UK (PDF)
- REACT long COVID (REACT-LC): led by Professor Paul Elliott, Imperial College London – £5.4 million over 3 years. The study will involve people in the community who have taken part in the REACT study of the virus that causes COVID-19. Data will be analysed to find common factors to examine why some people get long COVID and others do not. The biological studies will help us understand what causes persistent symptoms and may point to possible treatments
- Therapies for long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study): led by Dr Shamil Haroon and Professor Melanie Calvert, University of Birmingham – £2.3 million over 2 years. The study will identify which treatments are most likely to benefit people with particular symptoms of long COVID and test supportive treatments to improve their quality of life
- Characterisation, determinants, mechanisms and consequences of the long-term effects of COVID-19: providing the evidence base for health care services: led by Professor Nishi Chaturvedi, University College London – £9.6 million over 3 years. The study will use data from more than 60,000 people to help define long COVID and improve diagnosis. It will also explain why some people get the condition, the typical effects on a person’s health and ability to work, and the factors that affect recovery to inform the development of treatments offered to patients
- Non-hospitalised children and young people with long COVID (The CLoCk Study): Professor Sir Terence Stephenson, UCL Great Ormond Street Institute of Child Health – £1.4 million over 3 years. The study will teach us more about long COVID among children, how it can be diagnosed and how to treat it
COVIPS for Long COVID. First Vaccine Reaction Data for Long Covid | Pfizer, AstraZeneca and Moderna Analyzed
NHS may face a million long Covid patients after pandemic – The Guardian
Senior doctors are braced for up to a million people needing treatment for long Covid after the pandemic, putting huge extra pressure on an already overstretched NHS, the Guardian can reveal.
Long Covid is a significant problem affecting huge numbers of patients that will confront the NHS for many years to come, one of the service’s expert advisers on the fast-emerging condition said.
Signs are already emerging that the health service is having trouble keeping up with the demand for care created by the sheer number of patients who are still displaying symptoms such as exhaustion, brain fog, chest pains and breathing problems months after having Covid.
Doctors fear that staff shortages, the need to tackle the big backlog of surgery that has built up, and existing strain on lung and heart services will limit the care that the NHS can provide.
The boss of the hospital that set up the NHS’s first specialist clinic for long Covid admitted that it was struggling to give patients the speedy and high-quality help they needed. The head of the Royal College of GPs voiced concern that sufferers were facing long waits to get seen.
Prof Helen Stokes-Lampard, the chair of the Academy of Medical Royal Colleges, which professionally represents the UK’s 240,000 doctors, said: “The NHS knows this is a problem. It’s very concerned about this. Long Covid is going to be a very substantial new burden on the NHS. It’s working hard and setting up clinics. But there will be huge numbers of these cases and it’s clearly going to be dealing with this for years, absolutely for years.
“It’s going to be the next challenge that the NHS has to deal with whilst … recovering from the pandemic and whilst desperately trying to deal with the backlog [of diagnostic tests and surgery], with staff that are exhausted.
“People [in the NHS] are very fearful about how they’re going to be able to deliver [the care that long Covid patients need]. It’s going to be a bumpy ride.”
Stokes-Lampard is also a member of the taskforce that NHS England has set up to help it respond to long Covid.
The evidence so far shows that 20% of people who have had Covid still have some symptoms of it after four weeks and that 10% are still debilitated by it – sometimes very badly – after 12 weeks. While people who were ventilated in intensive care over the last year are the worst affected, some of those who never went to hospital are also having lingering symptoms.
One of Britain’s leading doctors, speaking on condition of anonymity, said: “Although officially about 4 million people have had Covid, in reality it’s about 8 million or 9 million. If 10% of those people have got something, then it could be almost a million people, and that’s enormous.”
Prof Martin Marshall, chair of the Royal College of GPs, said: “Right now there’s a lot of people in every GP practice that have got long Covid and who will develop long Covid. GPs are seeing growing numbers of people with post-Covid symptoms.” While about 300,000 people in the UK are thought to have long Covid, that is likely to rise, given the severity of the pandemic’s second wave, he said.
Some of the 40-50 patients with long Covid at his own practice in east London have been struggling to get an appointment at the first specialist clinic at University College London hospital, he said.
Prof Marcel Levi, UCLH’s chief executive, said: “It is fair to say that we are struggling to meet the demand of this patient group. We have a clear vision of the ideal pathway we would like to deliver. At the moment, we only have some of the components of that pathway in place, and it is something that needs rapid resource and focus to fill in the gaps.”
UCLH’s service, which opened in May, has already seen more than 1,300 patients. It expects about 1,000 new cases to present in the coming weeks. Access is restricted because of “workforce and resource constraints” and the team’s “significant backlog of other activity”, said Dr Melissa Heightman, the respiratory consultant who runs the clinic.
Stokes-Lampard and Marshall said that while NHS England’s creation of more than 60 specialist long Covid clinics was a good start, it would have to expand the care that was available.
Doctors are also worried that it is not yet clear how the NHS will be able to successfully treat those with long Covid, given its sheer array of symptoms and ongoing emergence as a condition.
Stokes-Lampard said: “It’s incredible that the NHS has set up and got going a network of new services in recent months. But the problem is that the services at the moment are only set up to assess people; there is no treatment known. It’s kind of still hitting a dead end because we don’t yet know how best to treat people. So we’re in a difficult situation as healthcare professionals.
“The diagnosis [of long Covid] is only part of the journey. It’s all about treatment and cure and actually we haven’t got many treatments and we haven’t got many cures. That is a concern.”
Long Covid poses a serious challenge for doctors to diagnose because so many of its symptoms, such as fatigue and pain, are also symptoms of so many other ailments, said Marshall.
Prof Andrew Goddard, president of the Royal College of Physicians, said: “It seems very likely that long Covid will place significant demands on the NHS moving forwards and given that many patients with long Covid did not get hospitalised and/or were relatively young, it shows the importance of vaccinating as much of the adult population as possible.”
NHS England said it planned to expand long Covid services this year and was still exploring what treatments worked best.
An NHS spokesperson said: “Long Covid is still a new condition, but dozens of NHS clinics across the country are rising to the challenge of understanding and treating it, bringing together expert clinicians to provide comprehensive assessments for thousands of patients, with more set to open over the coming months.
“We expect that there will need to be a substantial further expansion in support for long Covid patients during 2021. Covid and its long-term consequences are entirely new, but – through our network of clinics – the NHS is carrying out research and sharing learning about how best to treat and rehabilitate patients experiencing ongoing debilitating symptoms.”
It’s clear that vaccines have helped some people with long Covid with their symptoms. While the numbers are still small, these are encouraging signs. What follows is my hypothesis as to how vaccines might improve long Covid.
Back when I first learned about long Covid in June 2020, I proposed three possible mechanisms that might be causing it: 1) a persistent viral reservoir; 2) “viral ghost,” which are fragments of the virus (RNA, proteins) that linger after the infection has been cleared but are still capable of stimulating the immune system; and 3) an autoimmune response induced by the infection. Of course, other mechanisms may also contribute.
Since then, many studies have provided support for all three of these mechanisms. Research has shown that viral reservoirs are present in tissues, viral RNA is found in non-respiratory tissues and is associated with inflammation, and diverse autoantibodies are detected in some Covid patients.
The three mechanisms of long Covid I proposed above are not mutually exclusive, and all three may benefit from the vaccines. If the first is true, vaccine-induced T cells (immune cells that attack and kill infected cells) and antibody responses may be able to eliminate the viral reservoir. If the second is true, vaccine-induced immunity may be able to eliminate the viral ghost if such viral components are associated with the spike protein, which the virus uses to gain entry into cells. If the third is true, the vaccine might divert autoimmune cells, as I will describe below.
I suspect that people with long Covid have varying degrees of all three mechanisms taking place. Thus, long Covid consists of multiple types of diseases. By understanding which mechanism(s) are causing long Covid within each person, suitable treatment can be given.
To determine which mechanism(s) are responsible for vaccine-mediated improvement in long Covid, we can design a trial in which long haulers are given one of four vaccines.
Another possible way in which vaccines can help long Covid symptoms is through stimulation of innate immune responses, caused by the adjuvant component of the vaccines. Vaccines induce T and B cell responses. This requires two components, antigen (the stuff detected by T and B cell receptors) and adjuvant (the stuff that triggers innate immune responses).
Adjuvants stimulate the immune system by mimicking features of pathogens. Many vaccines are simply antigen combined with added adjuvant (like alum) — mRNA vaccines do not require extra adjuvant because the RNA itself serves as the adjuvant that stimulates the innate immune system.
Adjuvants can only induce transient inflammation. It could be that short-term inflammation caused by the adjuvant might somehow divert the leukocytes (immune cells) causing long Covid. If this is the case, the beneficial impact of vaccines may not be long lasting, because innate immune signals are temporary.
It is also possible that adaptive immune responses induced by vaccines divert the leukocytes causing long Covid. For example, antibody or T cell responses directed against a new antigen, regardless of what it is, might skew the immune system to shift its attention to the new antigen — though it is not clear for how long.
To determine which mechanism(s) are responsible for vaccine-mediated improvement in long Covid, we can design a trial in which long haulers are given one of four vaccines:
1. mRNA SARS-CoV-2 spike vaccine (the Covid-19 vaccine)
2. mRNA irrelevant antigen vaccine (e.g. Zika virus vaccine)
3. An empty mRNA vaccine (not coding for protein)
4. Placebo (saline)
The outcome of the trial can tell us both what may be driving long Covid as well as which therapies are likely to work best. Such a trial may be difficult for various reasons but is worth considering, as is the possibility of an animal model to try first. If only the mRNA coding for the spike protein (the Covid-19 vaccine) but not for an irrelevant protein (Zika virus) or empty mRNA helps people recover from long Covid, this implies the viral reservoir and viral remnant scenario may be the basis for long Covid.
If an empty mRNA vaccine (not encoding for a protein) improves long Covid, even transiently, such data imply that innate immune stimulation is able to reprogram the leukocytes causing the symptoms. If so, we can think of stimulating the innate immune system using empty mRNA or viral RNA mimic, or giving interferon-beta therapy periodically to improve symptoms. Interferon-beta therapy is also used to treat multiple sclerosis patients.
Lastly, my hope is that the data from such a trial might also inform treatment of chronic fatigue syndrome (ME/CFS), because people suffering from ME/CFS might have similar underlying causes of disease and therefore might benefit from similar treatments.