COVID19 vaccine inoculations are the best possible protection for most health profiles that science offers against this pandemic menace. However, as we know, COVID vaccines in their initially recommended dose schedules proved less effective in immunocompromised individuals. This was irrespective of whether poor immunity resulted from a medical condition or due to immuno-suppressive medication. Patients with advanced Chronic Kidney Disease & Kidney Transplant recipients are a prominent subgroup in this population subset of the “Vaccine Helpless”.
◾ So how did poor immunity in kidney patients impact vaccine effectiveness?
◾ Will repeated immune challenge with extra doses as part of primary vaccine series truly help all kidney patients? How tenable is it?
◾ Any better alternatives to garner adequate immune protection for our cohort without going overboard with the “immune challenge” and/or inviting side-effects of major concern?
Read on to decode the relevant science and understand your options for adequate immune protection against COVID-19.
(DISCLAIMER: The article is purely a medically feasible insight on current evidence from peer-reviewed scientific literature on COVID-19 vaccine efficiency, its shortcomings & potential relevant alternative pharmacological solutions w.r.t. patients with chronic kidney disease. The intention is to place the facts as they are with due respect to Science. It is not intended to promote any vaccine hesitancy or support anti-vaxxer views. It does not represent any political positioning either.)
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3. Way forward
THE SCIENCE & ITS CAVEAT
COVID Vaccine programmes worldwide extended vaccination to patients with advanced Chronic Kidney Disease & Kidney Transplant recipients on priority basis. This was because their weak immune status makes them more vulnerable to severe disease / death from COVID-19. However, this exercise was solely guided by logic without any actual trial data to guide on the clinical outcome of vaccine efficiency & safety. That’s because NONE of the COVID vaccine trials included CKD patients or transplant recipients for the obvious need for caution. Instead, the vaccination drive itself has virtually acted as a large trial on immunocompromised individuals & has been offering valuable insights to inform relevant clinical decision-making & health policy in future.
The healthcare machinery has been working on war-footing to attempt to protect the immunocompromised from the COVID menace. But as we know, the initially recommended COVID vaccine doses fell short in producing optimum immune response in these individuals. This was not completely unexpected though. The quality & duration of immune protection from vaccines completely relies on an intact, healthy immune system. This is precisely what’s lacking in this cohort.
In a nutshell, the very cause that makes persons with poor immunity vulnerable to COVID19 infection is also why the conventionally best possible protection against COVID19 (vaccines) proves ineffective.
But surely there’s more to it, right?
So, let’s dissect the mechanisms at play here to help you get an informed & logical take on relevant immune protection options that fit your case best.
POOR COVID VACCINE RESPONSE IN KIDNEY DISEASE: DISSECTION
I. In advanced pre-dialysis CKD
In CKD patients, prior history of natural COVID-19 infection significantly influenced vaccine-induced antibody numbers. Immunological memory from prior natural infection conferred an aggressive immune response in CKD patients over those who didn’t contract COVID-19. But irrespective of this observation, overall, vaccines fell short of inducing optimal immune protection against COVID-19 with their recommended dose schedules across all cohorts with advanced CKD.
The reasons below are why this possibly happened:
DIRECT KIDNEY DAMAGE IN CKD
In advanced Chronic Kidney Disease, there is extensive scarring (fibrosis) of both kidneys. This is irrespective of the root cause (Diabetes, Lupus, PKD etc.). Such over-enthusiastic scar tissue in-growth literally shoves & invades tiny spaces between the delicate “filter channels” present all along the fine tubes within the kidney.
Such massive scar tissue overgrowth ends up crushing the very filter channels that help kidneys function. As a result, kidneys lose the ability to apply the basic discretion of “what to let out and what to retain”. This causes two things:
Uncontrolled loss of plasma proteins in urine (including those critical to your immune system function as well as vaccine-induced anibodies)
Retention & buildup of metabolic wastes like Urea in blood which literally “suffocates” your immune system from producing normal responses.
UNDERLYING (ROOT) CAUSE FOR CKD
The root condition itself that caused CKD may also impact the functioning of the immune system directly. For instance, if CKD results from long-standing Diabetes, high blood glucose significantly “smothers” immune response over the long term.
GUT BARRIER DYSFUNCTION IN CKD
Chronic Kidney Disease compromises the intestinal barrier (internal lining of the gut) over time. This results in several nutritional deficiencies as well. Notably, with severe Vitamin D deficiency, immune system maturation takes a hit. That adversely impacts vaccine response.
IMMUNO-SUPPRESSIVE MEDICATION
Among a host of causes, Chronic Kidney Disease can result from a number of underlying inflammatory conditions. Such patients may be put on immuno-suppressive medication like Prednisolone, Tacrolimus, Cellcept (MMF) or even Rituximab. These directly weaken immune system activity & compromise vaccine efficiency.
All the above mechanisms act in tandem in advanced pre-dialysis CKD to dampen your immune response to the COVID vaccine. In addition, the vaccine induced anti-spike antibodies also end up circulating for a shorter time span. Hence, immune protection wanes faster over time than what clinical trials reported for healthy volunteers.
II. In CKD patients on Dialysis
Vaccinating patients dependent on in-center Maintenance Dialysis on priority was justified for reasons beyond poor immunity. Since these patients need to travel to their Dialysis Centers as opposed to those on Home-based Dialysis, their chances of exposure to COVID19 was exceptionally high. Moreover, where Dialysis centers relied on re-usable filters, things got complicated further.
Now, factors impacting immune response to COVID vaccines in CKD patients continue to persist even after starting Dialysis. However, although still suboptimal, the extent of COVID vaccine induced immune protection has been marginally better in CKD patients on Dialysis. This is because a dialysis machine is precisely adjusted to “define what to remove & what to retain”. Such controlled mechanical waste removal helps by:
Debulking the body of the excess urea load, hence immune cells are able to work in relative peace
Minimizing unchecked loss of immunoglobulins & immune-system supporting proteins in Urine. This ensures better retention of vaccine-induced immune protection.
III. In Kidney Transplant Recipients
Transplant patients with a normally functioning kidney graft are virtually free of mechanisms that impact COVID vaccine response during CKD. However, we are on “Therapeutic Immunosuppression”. That simply means, we need to take medicines to intentionally dampen our immune-system function to prevent it from attacking & rejecting our donor kidney. This regimen consists of a cocktail of “anti-rejection” meds that work by impacting both B-Lymphocytes (that form protective antibodies) & T-lymphocytes (that bring about cell mediated immunity or CMI).
To be more specific, here is how different Anti-Rejection medicines work:
With such potent immuno-suppressive agents at work, there is all round weakening of both T & B cell mediated immune pathways. Under such circumstances, any vaccine would be unable to produce optimum immune response. Expecting so would be akin to forcing someone with a fractured leg to win a sprint race alongside uninjured athletes. Both illogical & unfair.
To get a better antibody response, some medical centers opted for an immunosuppression bypass. They advised temporary dose reduction or halt immunosuppressive medication in transplant patients prior to their COVID Vaccine administration. The intention was noble. However, was giving precedence to vaccine-induced COVID antibody response at the cost of making the life-saving donor organ vulnerable to immune-mediated damage & rejection by stopping anti-rejection meds was not a risk worth taking. Instead of tweaking the medicine dosage, vaccine alternatives that make immune protection last despite continued immunosuppression is a better approach.
NEED OF THE HOUR
Everyone needs & deserves to be optimally protected from the menace of COVID-19.
COVID vaccines are arguably the best tool that science has to offer in this regard. However, we must consider the following:
🟫 The quality & duration of immune protection with currently available COVID vaccines varies with individual health profiles & the vaccine brand used. Hence standard dosing will not help each vaccinated individual equally.
🟫 Safety, immunogenicity & efficacy data of COVID vaccines is dynamic & continuously evolving.
🟫 Vaccines require continuous up-gradation with emerging new variants of the virus. Vaccines taken today may show less efficiency with newer variants of the future due to new gene mutations in the viral structure, not included in the present-day vaccine product.
Current COVID19 Vaccines are safe in the short-term & effective for most health profiles unless newer variants-of-concern emerge. However, pharmacovigilance inputs after COVID inoculations have raised concerns among certain patient sub-groups.
For instance, multiple medical centers worldwide have reported on mRNA based COVID vaccine inoculations flaring up glomerular diseases like IgA Nephropathy & Minimal Change Disease both in Pre-transplant CKD patients & kidney transplant recipients. Most of these patients with IgA Nephropathy relapse presented with complaints of blood in urine. When tested, their urine was positive for both blood cells and increased protein leak in urine. In some cases, there was also a rise in their serum Creatinine levels. Upon treatment with steroids or other immunosuppressants, gross hematuria (blood in urine visible to the naked eye) subsided, quantity of protein loss in urine and serum creatinine levels reduced. However, microscopic hematuria persisted indicating added kidney damage.
Active immunization with many vaccines (not just COVID-19 vaccine) have associated concerns of triggering relapse of or aggravating IgA Nephropathy. These include, but are not limited to Pneumovax, Influenza (Flu), Shingrix (against Shingles), Hemophilus influenzae type B (HiB) and Meningitis (N. meningitidis) shots. This is possibly because vaccine-induced molecular pathways in immune response share inflammatory pathways in autoimmune conditions. However, the exact mechanism is a subject of active research.
These valid concerns have also been balanced with counter-opinions. These state that the benefit of COVID19 vaccination exceeds the “theoretical” risk of developing a “manageable” complication like IgA Nephropathy relapse. This counter-view would’ve been tenable if it came through in March 2020 when there was no cure or effective treatment for COVID-19.
But at this point in November 2021 w.r.t. immunocompromised individuals:
🟫 COVID vaccines have fallen short of offering adequate immune protection in CKD patients (pre-dialysis, on dialysis, post KT). The need for adherence to COVID appropriate behavior (wearing a mask, handwashing/sanitization & avoiding crowds) still stands as an essential protective measure in this cohort.
🟫 There are effective anti-virals & treatment protocols in place for COVID-19. The latest one is the anti-viral drug Molnupiravir with specific Anti-COVID activity.
🟫 Complications like IgA Nephropathy triggered with COVID-19 vaccines (mostly mRNA based) have been reported across geographies. It is not theoretical. In addition, although IgAN relapse is a manageable complication, it is still INCURABLE. This is especially a concern for kidney transplant recipients. Any IgA Nephropathy relapse essentially means triggering chronic allograft nephropathy (Chronic rejection) of the transplanted kidney graft. However, the disease course is likely to be indolent due to immunosuppression from anti-rejection medicines.
All these contentions & caveats require researchers & policymakers to re-think their strategy for the immuno-compromised kidney patient subgroup.
The obvious need of the hour is to ensure immune protection in this patient cohort that is both as potent and as long-lasting as in healthy volunteers if not more. However, this must NOT be at the cost of triggering any adverse effects of major concern in the long run.
WAY FORWARD
Taking reported contentions into consideration, the following methods have found support with the research fraternity & policymakers alike:
METHOD 1: EXTRA VACCINE DOSE AS PART OF PRIMARY-SERIES
= Extra dose over and above the recommended initial primary dose schedule to achieve optimum immune protection in immunocompromised individuals.
This is different from a Booster Dose which means providing extra vaccine shots to healthy individuals afterwards when optimum immunity achieved from their primary vaccine doses wanes off over time.
Over the last few months, some countries such as France, UK & Israel have gone ahead with a third & even fourth dose of COVID mRNA vaccines. Recently, the US FDA has approved “Third primary series dose” for all immunocompromised individuals inoculated with mRNA vaccines, aged 12 years and above.
Boosters and added doses as part of primary vaccination series diversify the “immune challenge”. Hence it is logical to expect greater antibody titres after this dose as compared to the primary dose series. Trial data on immunogenicity of the third primary dose for the immunocompromised & Booster doses meets these expectations.
But please note, Clinical trials for a COVID Extra Primary Series Vaccine doses by mRNA vaccine brands like Pfizer® have been for a limited duration before receiving emergency use approvals. Hence there is no conclusive data yet, on how long the extended immune coverage may last in kidney patients in field conditions. The 1st batch of extra primary dose volunteers are being studied in real time to analyze the clinical outcome. Renal transplant recipients who have been inoculated with the 3rd vaccine dose in certain centers have reported suboptimal antibody titres again.
But, is such “repeated immune challenge” a credible solution to ensure adequate, lasting anti-COVID19 immune protection in all immunocompromised persons?
Is there potentially a better alternative that is less likely to aggravate preexisting incurable medical conditions?
Perhaps there is, as explained below.
METHOD 2: “READYMADE” ANTIBODIES (PASSIVE IMMUNIZATION)
= Lab made monoclonal antibodies mimicking natural antibodies against COVID19
Monoclonal antibody cocktails like the ones from Regeneron® or Roche® are now being used on immunocompromised individuals exposed to COVID-19. These are extremely efficient in neutralizing the virus in the bloodstream & relieving symptoms. Results remain comparable both in out-patient & in-patient use.
So the question that naturally arises is, could these “Readymade Antibodies” function like vaccines & offer necessary anti-COVID immune protection in immunocompromised individuals for adequate duration BEFORE any kind of exposure to COVID19?
The answer to this question depends on how long the various Monoclonal Antibody Cocktails with potential anti-COVID activity circulate in the bloodstream.
The ones currently in use are short acting ones. Meaning, if you administer them as “pre-exposure prophylaxis”, they are likely to protect you only for a few weeks at which point, you need a repeat booster dose. This is untenable / unsuitable for a “vaccine-like” regimen.
So, the research fraternity has now turned towards what we call “Long Acting Antibodies” or LAABs with anti-COVID19 activity.
Drug maker Astra Zeneca has an ongoing study called the PROVENT Trial involving two LAABs namely Tixagevimab & Cilgavimab. The combination therapy is tentatively named AZD7442. These Antibodies are pitched to stay in your system for about 12 months with one dose. Recently, PROVENT Phase III trial indicated 83% reduction in risk of developing symptomatic COVID-19 in immunocompromised volunteers compared to placebo group. Based on these encouraging data, the company filed an application for Emergency Use Authorization (EUA) for AZD7442 with the USFDA.
UPDATE: AstraZeneca®’s Long Acting Antibody (LAAB) combination drug brand named Evushield® has been granted Emergency Use Authorization by US FDA on 8th December for use in immunocompromised adults and certain paediatric cases in the US.
LAABs are readymade & protection-ready antibodies. So, unlike vaccines, they do not present an immune challenge to coax your immune system to generate any more of protective antibodies. This means, the usual vaccine-induced antibody generation pathways that share inflammatory pathways in autoimmunity are NOT activated with LAABs. As a result, Passive Immunization with LAABs is expected to be safer in patients with conditions like IgA Nephropathy that flare up due to active immunization with vaccines. Ongoing clinical trials will shed more light on this matter as they conclude in June 2022.
TAKE HOME MESSAGE
COVID19 Vaccines need an intact immune system to offer optimal immune protection against natural infection. However, at all stages of CKD whether pre-dialysis, on dialysis or post kidney transplant, there exists a certain degree of immunocompromise via different mechanisms. This is why, none of the current COVID19 Vaccines administered in their initially recommended primary one or two-dose schedules proved sufficiently effective as a “standalone measure” in protecting against natural COVID-19 infection in this cohort.
Covid appropriate protocol (wearing a mask, handwashing/sanitization & social distancing) remains an essential approach that this patient subgroup needs to adopt regardless of their vaccination status.
To aid this situation, healthcare policymakers worldwide are now pinning their hopes on increasing the “immune challenge” to trigger greater anti-spike antibody numbers or offering “readymade immune protection” in the immunocompromised kidney patient cohort.
Clinical trials and post-emergency-use-approval inoculation drives with Three dose primary series vaccines, Boosters & Passive Immunization with Long Acting Antibodies (LAABs) are currently underway. Some of these include patients with CKD. Data collated from these trials/vaccination drives will offer clearer insight on how these techniques fare in the CKD cohort. Of special interest would be data on kidney patients with autoimmune conditions like IgA Nephropathy or Lupus that showed sporadic flare-ups across the world following initial inoculations with COVID vaccines currently in use.
We firmly believe in the fundamental right to equitable immune protection against a global pandemic. What actually protects practically at the clinical level as per individual health profile is what makes for the most sensible approach. This calls for case-by-case evaluation for personalized vaccine effectiveness instead of applying generalized scientific rationale en-masse. True, vaccines are the best possible protection against COVID19 in the majority of health profiles. But where vaccines fall short of conferring adequate relevant immune protection, passive immunization techniques must be considered as an alternative (not only as adjunct). This is more so in the subgroups where vaccines end up aggravating a separate pre-existing medical condition like IgAN that’s manageable but INCURABLE.
Here’s hoping that unadulterated, practical, clean science manages to stay above any reporting bias, undue commercial interests or political pressure, & immunocompromised individuals get their due in this fight against the pandemic.