RBDCOV: It Starts and Ends with Us | Why RBDCOV and Other Vaccine Development Projects Need to Consider “Long COVID” and Pre-existing Comorbidities

Since the start of the COVID-19 pandemic, vaccines have saved millions of lives by preventing severe illness and death. Throughout the course of the EU-funded RBDCOV project, members of the Community Advisory Panel (CAP), have worked alongside the research team to develop next-generation protection for vulnerable populations, including people living with HIV and autoimmune kidney disease.

Autoimmune kidney diseases, like lupus nephritis, vasculitis, or IgA nephropathy, happen when the immune system mistakenly attacks the kidneys. Managing these conditions often requires a broad range of medications that can suppress the immune system to control inflammation, and this can make it harder to fight off infections and viruses like COVID-19.

For many patients living with autoimmune kidney disease, the COVID-19 pandemic brought considerable additional risk. Early data indicated that 2 out of 5 patients in the UK on kidney dialysis died in the first wave, before vaccination, according to UK data from Kidney Care UK and that hospitals had to repurpose equipment in order to tackle the COVID-19 pandemic, which had a significant impact on people’s mental health.

The European Kidney Health Alliance (EKHA) found that transplant patients were among the highest-risk groups, with the highest mortality. It has called on policymakers to increase sustainable investment in preventive strategies for chronic disease management to better protect patients during upcoming infectious waves and improve health outcomes of the population in the future.

Moreover, many research studies have not yet looked at autoimmune disease population cohorts in sufficient detail, particularly regarding both protection and long-term effects from COVID-19 infection. The RBDCOV project was different in this sense because its clinical trial included people on dialysis (treatment that takes over some of your kidneys’ function) and people who had a kidney transplant and were receiving chronic treatment to avoid organ rejection.

Patients with autoimmune kidney disease may have different levels of protection afforded to them from the vaccines themselves and may not even get as full immune response. Still, some protection is better than none. Studies reporting immunogenicity in immunocompromised patients have been too heterogeneous to support robust conclusions. However, there is some indication that the BIMERVAX, the vaccine studied in RBDCOV and approved by the EMA, may offer additional efficacy in this vulnerable group by improving seroconversion rates.

“Post-COVID-19 condition”

However, many questions remain unanswered. Death and severe illness are not the only outcomes that matter, and emerging evidence has long shown that they are only a part of the story. The WHO has defined post-COVID acute sequelae, also known as post-COVID-19 Condition or “Long COVID”, as a condition affecting a condition affecting millions of people, including those who had experienced only a mild infection and were not hospitalised. Five years in, we understand a bit more about the disease’s pathology, yet the suffering of thousands remains insufficiently addressed.

Symptoms of “Long COVID” can be far ranging and affect different systems in the body, including neuro-immunological, vascular endothelial and inflammatory processes, to name but a few. Some studies have identified more than 115 different types of symptoms. Yet, there is still no universally agreed set of common metrics to measure them. The SBQ (Symptom Burden Questionnaire) for “Long COVID”, which I contributed to, attempts to address this gap by developing a patient-reported outcome (PRO) tool for the condition and I am pleased to see clinical trials in the US take a different approach towards examining the broad interplay of factors affecting the pathophysiology. Several patients living with “Long COVID” have developed autonomic dysfunction and research from the primary care association of general practitioners in Spain has found that this can be as much as up to 84%. The American Autonomic medical bodies have named “post-COVID POTS” as the newest phenotype of Postural Orthostatic Tachycardia syndrome.

For patients living with POTS, Postural Orthostatic tachycardia syndrome, it has been great to see more recognition and awareness of the condition. There is still a considerable need for medical training to improve patient access to appropriate healthcare professionals, an initiative long supported by EFAS, the European Federation of Autonomic Societies as at least 2/3 of European countries lack the provision of dedicated autonomic medicine centres. Even in countries with cardiologists and neurologists that have an interest in this area of medicine, the waiting lists are very long, and patients often require multi-disciplinary integrated care, which can vary from each country. In the UK for example the BMJ found that the average time to diagnosis for POTS pre-pandemic was between 4-7 years. In addition, POTS currently has no approved medications at the EMA, FDA or MHRA levels, and there are often issues when patients present with more than one condition in terms of appropriate medication as primary care do not necessarily feel comfortable adjusting medications in the interim period waiting for follow up. “Long COVID” therefore presents a unique opportunity to better research and improve quality of care for patients with a broad range of complex chronic diseases that have historically been overlooked.

Vaccine protection against developing “Long COVID” depends on several confounding variables, including but not limited to the type of vaccine, the timing of its administration, the circulating COVID-19 variant, and the person’s specific immune system.

This variability needs to be considered more broadly in future vaccine development. Personalised medicine approaches need to be tailored to consider broader divergence. For example, whilst patients with autoimmune kidney disease may have suppressed immune systems, requiring vaccines that enhance immune responses, for some patients living with POTS and “Long COVID”, the opposite may be the case. For example, patients living with both POTS independent of Covid-19 infection and sometimes alone can have another comorbid condition such as Mast Cell Activation Syndrome (MCAS), with a highly sensitised and reactive adaptive innate immune system. This would require an adapted approach to vaccine development. It is also important to acknowledge the differences in disease pathology and symptom expression among “Long COVID” patients This complex heterogeneity and its multifactorial nature make the condition particularly difficult to study and manage.

Future research

Patient advocacy groups have long called for better tracking of severity, duration and incidence of “Long COVID” over time. However, political barriers have made this far from reality. Projects like RBDCOV can make a real difference, if they measure what matters. As demonstrated by the involvement of the Community Advisory Panel (CAP), collaborative efforts are essential to ensure alignment between objectives across different stakeholders.

Future vaccine development efforts and trial design, particularly in relation to POTS and other aspects of “Long COVID” should consider adaptive platform trials with basket designs capable of addressing the outcomes that matter to patients. A deeper understanding of the differentiated levels of risk and protection is needed when it comes to “Long COVID”. Ultimately, vaccine research design should not follow a one-size-fits-all model, but rather a personalised approach, one that patients are actively asking for. Patients need clear guidance based on real-world data, with real solutions that lead to meaningful change. There is still a long way to go in addressing the unmet needs around POTS and “Long COVID”

Jennifer Camaradou

Innovation & Patient Engagement in Research Consultant and RBDCOV Community Advisory Panel member

Research Gate profile: https://www.researchgate.net/profile/Jennifer-Camaradou

Disclosure message: I am writing this in an independent capacity, current member ESC European Society of Cardiology Patient Forum, former lay member UK NICE Covid-19 expert panel. Views are my own.

REFERENCES

1. Kidney Care UK. (n.d.). How does kidney disease affect my risk from COVID-19 and how do I manage my risk? Retrieved from https://kidneycareuk.org/kidney-disease-information/about-kidney-health/covid-19-and-kidney-disease/how-does-kidney-disease-affect-my-risk-from-covid-19-and-how-do-i-manage-my-risk/
2. European Kidney Health Alliance (EKHA). (n.d.). Homepage. Retrieved from https://ekha.eu/
3. World Health Organization (WHO). (n.d.). Post COVID-19 condition. Retrieved from https://www.who.int/europe/news-room/fact-sheets/item/post-COVID-19-condition
4. NHS. (n.d.). Postural tachycardia syndrome (PoTS). Retrieved from https://www.nhs.uk/conditions/postural-tachycardia-syndrome/

This blog is part of the RBDCOV campaign ‘It Starts and Ends with Us’ 

The RBDCOV project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101046118

Views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.