A few words about the state of SARS-CoV2 science
Before we start reviewing the literature it is important to recognize the current landscape of peer review (or lack thereof). Especially in the fast moving world of COVID-19 research. Brian Byrd provides a nice overview for our readers here. The differences between preprints, letters to editor, rapid response and other publication types are discussed detail there.
Updated July 28, 2021: Added third dose studies, large case series on breakthrough infections
Curated and Edited by
Swapnil Hiremath, MD, MPH, University of Ottawa, Canada
Joel Topf, MD, FACP Oakland University William Beaumont School of Medicine, Rochester, MI
Contributors/Reviewers
Edgar V. Lerma, MD, FASN University of Illinois at Chicago/Advocate Christ Medical Center, Oak Lawn, IL
Graham Abra, MD Stanford University and Satellite Healthcare, San Jose, CA
Christos Argyropoulos, MD, University of New Mexico Health Sciences, Albuquerque, New Mexico
Matt Graham-Brown, MD, PhD, NIHR Clinical Lecturer, Leicester, UK
Andreas Kronbichler, MD, PhD, Cambridge University, UK
Ed J Carr, MD, PhD, Francis Crick Institute, London, UK
Michelle Willicombe, MD, Imperial College, London, UK
Rita Suri, MD, McGilll University, Montreal Canada
General COVID vaccine resources
NY Times Vaccine tracker
UK Govt Green Book Chapter 14
CDC page on COVID vaccines
Carlo Graziani’s Covid Vaccine Efficacy Blog
Covid Vaccine in Kidney Disease Resources
NKF Page
Vaccine FAQs from the Ontario Renal Network (PDF link)
American Society of Nephrology Toolkit Vaccine page
American Society of Transplantation Vaccine FAQs
UK Renal Association FAQ page for staff and patients
High Yield Twitter Accounts
Hilda Bastian @hildabast
Derek Lowe @DerekLowe
Florian Krammer @Florian_Krammer
A note on COVID vaccine efficacy data
Vaccine Basics
Hilda Bastian has the most comprehensive running blog on the vaccine story from its beginning roughly a year ago (Absolutely Maybe, March 16 2020).
Derek Lowe’s blog has many posts, which get into the details of vaccines, especially production and many more details from the pharmaceutical angle.
These images from Florian Krammer’s review in nature (Krammer et al, Nature 2020) give a quick overview of all the vaccine platforms.
Figure from Krammer et al, Nature 2020 showing the different vaccine platforms
Figure from Krammer et al, Nature 2020, showing how the rapid development of vaccines was possible
Table showing different vaccine platforms
Interpreting Efficacy
How should you assess efficacy of COVID vaccines? From an RCT of placebo compared to vaccines and subsequent infections and disease, right? As you can see above, none of the vaccine trials included CKD patients, especially those on dialysis or transplant, typical of the renalism often seen. So we rely currently on surrogate outcomes. Such as antibody titres, and cellular responses. These do not necessarily mean the same thing as efficacy, so take that into account while reading the serological data presented below.
Other factors that are important are:
When was the antibody titre measured? As can be seen in one of the studies below (Attias et al, Kidney Int 2021), these titres will be different at different times
What was the underlying community prevalence? It is possible some patients may have had prior asymptomatic infections, and hence might mount a robust response after one dose
Is it an IgG or an IgG/IgM? Remember IgM rises quicker after exposure than IgG, so expect to see higher levels with those tests
Is the actual antibody titre important or a threshold? Some studies report ‘any detectable’ antibody, other report a neutralizing titre, or a numerical threshold - reminding one of the infamous dichotomonia warning
There is inter-assay variation that might explain some of the variation than a true biological effect
Lastly, even at a low or undetectable circulating antibody titre, the memory B cells might still remember and mount an antibody response. There is so much more to immunity than a serological response
Some of these issues are discussed in this excellent twitter thread:
An excellent editorial in Kidney International (Ikizler et al, Kidney Int 2021) discusses these issues and is worth a careful read. See a table below from the same publication:
Table from Ikizler et al, Kidney Int 2021
For a longer explanation, read Ed Carr’s explainer post:
Covid Vaccine Efficacy in Dialysis
This is a summary of the data we have so far, and we will try to keep it updated as more papers get published. Note that most, if not all, of the data is on antibody response, with some on cellular response - so all surrogate outcomes, as expected with the small numbers studied. The assumption here is that antibody response and/or cellular response truly reflect protection against infection or disease.
Table showing the vaccine data in dialysis patients
Sources: Goupil et al, MedRXiv 2021; Simon et al, MedRxiv 2021; Schrezenmeier et al MedRxiv 2021; Grupper et al, cJASN 2021; Agur et al, NDT 2021; Sattler et al MedRxiv 2021; Lacson et al MedRxiv 2021; Torreggiani et al, Kidney Int 2021; Attias et al Kidney Int 2021; Billany et al Kidney Int 2021; Berar Yanay et al Kidney Int 2021; Frantzen et al NDT 2021; Rincon-Arevalo et al, MedRxiv 2021; Jahn et al, Vaccines, 2021
In summary, it seems as if the response after 1 dose is suboptimal, ranging from 18 - 44% (with one outlier at 74%, but which measured the IgG/IgM, which could explain the difference), which improves after 2 doses (range 80 - 96%). Note that time after vaccination till antibody response is seen matters - and the low response after 1 dose may partly reflect that (also see figure below). Specifically, in the Goupil et al study, after one dose, there was no increase in antibody response at 8 weeks (orange, below) compared to 4 weeks (red).
Figure from Goupil et al, MedRxiv, 2021 to demonstrate lack of response at 4 weeks persists at 8 weeks after 1 dose
Additionally, even after 2 doses, the magnitude of serological response is less than what is seen in nondialysis patients in almost all studies. This of course, is immune response and not actual efficacy in preventing disease or infection. One study does have both the adenovirus or the mRNA platforms and didn’t note any notable difference in antibody response (Billany et al, Kidney Int 2021). Still early days and small numbers.
From Attias et al, Kidney Int 2021
Serological response after first and second injections of BNT162b2 mRNA Vaccine in patients with or without previous history of COVID-19. Comparison of the evolution of SARS-CoV-2 ant-spike antibodies over time (days) after first (Day 0, blue arrow) and second (Day 28, red arrow) BNT162b2 mRNA Vaccine between group with previous COVID-19 (n=13) and group with no history of COVID-19 (n= 57).
Covid Vaccine Efficacy in Transplant
There are a few studies in kidney transplant recipients, a couple after a single dose, and the others after 2 doses, all with an mRNA vaccine. Unfortunately, they all report a poor effect in terms of antibodies and cellular response, as seen below:
Sources: Sattler et al, MedRxiv 2021; Boyarsky et al - 1, JAMA 2021; Benotmane et al (one dose), Kidney Int 2021; Grupper et al Am J Transplant 2021; Benotmane et al (2 doses) Kidney Int 2021; Marinaki et al Am J Transpl 2021; Husain et al KI Reports 2021; Rincon-Arevalo et al, MedRxiv 2021; Chavarot et al, Transpl 2021; Yi et al, Transpl 2021; Cucchiari et al Am J Transpl 2021; Marion et al, Annals IM 2021; Korth et al, Viruses 2021; Rozen-Zvi et al, Clin Micr Inf 2021; Boyarsky-2 et al, JAMA 2021; Ou et al, Transpl 2021
Thus the overall range after 2 doses seems to be 2.5 to 59% for antibodies, with impaired cellular response as well (3 studies). This of course, is immune response and not actual efficacy in preventing disease or infection.
See this discussion thread for more details. It is possible that the immunosuppressive agents interfere with the antigen presentation with the mRNA vaccines. It would be crucial to examine if this is also seen with the adenovirus vector vaccines, and with the inactivated protein (eg Novavax) and inactivated virion (eg Sinovac or Covaxin) platforms as well.
What are the risk factors for a lack of antibody response? So far we have seen
older age
triple immunosupression
MMF use
high dose steroids
Belatacept (Chavarot et al, Ou et al, Husain et al)
as being associated with a lack of robust antibody response.
Breakthrough COVID-19 after Vaccination
In addition, we also have quite a few published reports on the occurrence of COVID after vaccination.
Two of the studies discussed above reported COVID infections. in the study from Grupper, 2 (of 136) developed COVID; in the one from Rozen-Tvi, 4 (of 308) developed COVID and in this study, three had severe disease and one died.
All 7 of the patients described in this small case series from Mayo (Wadei et al, Am J Transpl, 2021) had received the mRNA vaccines (5 with 2 doses, and 2 with 1 dose) and developed COVID. 5 of these patients required hospitalization, 4 with hypoxemia and 1 with AKI. Fortunately, they all recovered with the management provided.
13 patients described in a case series from Columbia (Tsapepas et al, AJKD 2021). 8 had received both doses of the mRNA vaccines, 1 had received the J and J vaccine, and 4 had received 1 dose of the mRNA vaccines. A total of 904 patients were vaccinated at the centre, so 13/904 (1.4%) is a small proportion, of whom 7 fit the CDC definition for breakthrough. 3 patients required hospitalization, of whom 2 required ICU care, and one died.
55 patients from a centre in France developed COVID after 2 doses of an mRNA vaccine (Caillard et al, Kidney Int 2021). 11 of them required hospitalization, 6 ICU care, and 3 died. 25 had antibodies measured, of whom 24 had absent response, and one had a weak titre.
In a study from Song et al, 7 of 380 vaccinated patients (2 with mRNA-1273, and 5 with BNT162b2) developed COVID, with 4 requiring hospitalization
From this study of 2350 KTRs (Tau et al, Am J Transpl 2021) who had received atleast one dose of an mRNA vaccine, 25 developed COVID; of whom atleast 18 had had 2 doses. 10 of these developed severe disease, and 7 of them died.
14 patients in this case series (Ali et al, Transplantation 2021), all with 2 doses of an mRNA vaccine, of whom half required hospitalization and 1 died
A case series from India (Meshram et al, Transplantation 2021) with the adenovirus vector vaccine (Covishield/AZD122) of whom 2 developed after one dose and 2 after 2 doses. At the time of reporting, one had died, two were on mechanical ventilation and one recovered.
A large case series (Qin et al, Transpl 2021) collates data from 17 centres (including USA, Israel, Croatia and France - and possibly including some mentioned above). Of 18,215 SOTR with 2 doses, there were 151 (0.83 %) breakthrough infections, 87 (0.48 %) requiring hospitalization and 14 of whom died. Thus mortality among those with breakthrough infections despite two vaccine doses was 9.3 % (14/151).
See thread below for more discussion.
What should we do then? We do need to test some alternate strategies:
Would a non-mRNA vaccine (eg the Novavax, or the adenovirus vector platform) work better?
Add a third dose (since there seems to be some additional conversion after 2nd dose)? See a notable N = 1 case report
Would a mix-n-match, i.e. heterologous strategy be more efficacious than the same vaccine platform for prime and boost?
Hold the antimetabolite and then vaccinate? Trade-off of higher risk of rejection (see Knoll et al JASN 2003)
Third Dose Studies
These are coming in fast. The same caveats apply, that they measure antibody response. Please read Ed Carr’s blog if you haven’t already, first.
Sources: Werbel et al, Annals 2021; Kamar et al NEJM 2021; Benotname et al JAMA 2021
Lack of response seems to be associated with similar factors including age, intensity of immunosuppression (including triple IS and/or belatacept), lower GFR, and lower antibody titre after 2nd dose. Only one study including heterologous vaccines (Werbel et al, Annals 2021) and it is still too early to comment on the efficacy of that strategy.
Overall, among all transplant recipients, vaccine response increases from ~ 40% to ~ 70%. If one includes only 2 dose non-responders, about 50% of them respond to a third dose. Not perfect, but quite encouraging.
COVID Vaccine Efficacy in non-dialysis CKD
Little data exist in this population. The caveats about older age being a factor associated with a poorer immune response likely apply. But what about the role of immunosuppression, eg in patients with glomerulonephritis? A preprint in patients with chronic inflammatory diseases (Parakkal et al, MedRxiv 2021) provides useful information in this setting. Note that of these 133 patients, most had inflammatory bowel disease or rheumatoid arthritis, and 15 had SLE, so this is an extrapolation to CKD patients with GN. However, overall the authors report a blunted immune response in terms of antibody production, which was greatest with B-cell depletion therapies, followed by steroids. It is not known how soon after B-cell depletion did these infections occurred, and consensus is emerging to give vaccines 4-5 months after Rituximab.
Table 2 from Parakkal et al, MedRxiv 2021
In addition, Dagan et al (NEJM) published the initial results from the mass vaccination in Israel, using a matched cohort design (i.e. it was not a trial). In the subsequent correspondence (Dagan et al, NEJM 2021), they provide some subgroup data, as shown below. Reassuringly, these provide data on high efficacy in infections and severe infections in CKD and immunosuppressed patients (which includes organ transplant recipients). However, note the large confidence intervals and the small numbers in those rows - suggesting that we really don’t know much at this stage.
From Dagan et al, NEJM 2021. Note the rows for CKD and Immunodeficiency (red dots). CKD was defined based on ICD codes, so we do not know what GFR they represent. The blue dots shows the efficacy data - and the wide CI denote the likely low numbers in these subgroups.
Safety of Vaccines
Overall Safety
coming soon
Glomerulonephritis: New and Relapse
Case reports are trickling in, summarized below.
Sources: Mass et al, AJKD 2021; Lebedev et al, AJKD 2021; Komaba et al, AJKD 2021; Agati et al, Kidney Int 2021; Kervella et al, Kidney Int 2021; Aydin et al, Kidney Int 2021; Gul Rahim et al Kidney Int 2021; Negrea et al, Kidney Int 2021; Tan et al, Kidney In 2021; Masset et al, Kidney Int 2021; Morlidge et al Kidney Int 2021; Sacker et al, Kidney Int 2021; Weijers et al, Kidney Int 2021
Thus so far, we have
10 cases of MCD, 5 which were relapses and 5 new diagnoses, 4 of the new diagnoses with concomitant AKI; almost all responded or are responding to steroids; 3 vaccine types (mRNA and one with the adenovirus vector platform)
6 patients with known IgA who developed immediate gross hematuria which spontaneously resolved (all mRNA)
6 RPGN presentations: 2 with IgA, 2 with anti-GBM (one with additional mesangial IgA) and 2 with c-ANCA vasculitis (all mRNA)
A membranous relapse (with Sinovac) and an IgG4 nephritis relapse
While these may look impressive, keep in mind that they are reports of a few cases after a many millions of vaccine doses. So they could represent just the underlying incidence of disease. One could also argue that all GN cases may not get published, so the true incidence could be higher. A case could also be made that the vaccine induced immune response may trigger certain GN mechanisms. These do not take away from the clear need to vaccinate all individuals, including those with existing glomerulonephritis. There have been many cases of GN occuring after COVID - and the risk of GN after vaccination is likely to be lower (apart from vaccination helping one to avoid all the other baggage that comes with COVID itself).
A vaccine-GN registry, or a good longitudinal cohort study, would be helpful to help us understand how much of a true phenomenon this is, and track outcomes.
Acute Rejection
coming soon
Patient FAQs
Should I get the COVID vaccine?
Yes.
Does it matter which COVID vaccine I get?
A bird in hand is worth two in the bush. For now, get the vaccine you have access to. However, do watch this space. If there is information in the future that shows one form of vaccine being more protective than another, we will clarify that point.
Will the COVID vaccine give me COVID?
No, the vaccine will not give you COVID. The vaccines are designed to help your body’s immune system fight against COVID, so they boost your body’s natural immunity to kill the virus, and decrease the chance of getting severe COVID disease.
How well does the COVID vaccine protect me against COVID?
Unfortunately at this time, we do know that the immune response of your body to the COVID vaccines is not the same as is seen in the general population. See the data above for more information. This may be due to various factors including
Kidney disease results in a weaker immune system
Immunosuppressive drugs (eg anti-rejection drugs) also weaken the immune system and the body’s ability to react to a vaccine
What is the effect of the variants on vaccine efficacy?
Among many other things, this is one of the unknowns. There is some data to support that some variants have immune escape, ie, they result in reinfections and some vaccines do not work in them (e.g. the B 1.351 first described in South Africa and the Astra Zeneca adenovirus vector vaccine). These vaccines may still offer some protection against severe disease, but modified vaccines are already being tested which are likely to be effective against these variants.
Does the schedule (i.e. timing of second dose) matter for its effect?
In hemodialysis patients, a stronger immune response (i.e. more protection against COVID) was seen after the second dose. Among transplant recipients, the response does not seem very strong even after a second dose. Nevertheless, there is a greater response after 2 doses compared to one dose, so it is important to get the two doses as scheduled without any delay.
Can I stop wearing a mask and stop shielding or social distancing after getting the vaccine?
Ideally, getting the vaccine means you are protected and invulnerable to COVID. Unfortunately, the vaccines are not 100% efficacious in protecting, and if the community prevalence of COVID is high, then the chances of getting COVID despite vaccination are not insignificant.
Additionally, as noted above, the vaccines effect in kidney disease seems to be less especially in those receiving immunosuppressive drugs, especially kidney transplant recipients. Even in dialysis patients in whom a good response is seen, it takes longer to see this, so instead of the 2 week delay, this may be 4 weeks until the vaccine starts protecting you.
Hence it would be safer to continue with the precautions atleast until the community level of COVID is low in your area, and follow your kidney/dialysis/transplant team’s advice. It is also very important that people around you (i.e. family members, or individuals living in the same household) get fully vaccinated as soon as possible.
What are the side effects of the vaccine in people living with kidney disease?
None of the trials were done in patients living with kidney disease. Hence we cannot say with certainty what side effects and reactions will be seen specifically. Overall, the risk of adverse events with COVID vaccines in the general population is very low, and these are quite safe. A report of 741 solid organ transplant recipients suggests that the most common side effects (from the mRNA vaccines) are similar as seen in the non-transplant population, including local pain being the most common, and feverm, myalgia following behind (Ou et al, Transpl 2021).
Additional FAQs
Also see these Vaccine FAQs from Kronbichler et al (NDT, 2021)
Vaccine Progress Worldwide
List of Updates:
April 19 2021: Page created
Apr 20: Links to UK Govt green book, CDC, and UKRA FAQs added; many studies from Kidney Int added; caveats to interpreting serology, contributor list
Apr 22: addition of data from Dagan et al NEJM
Apr 23: addition of data from Husain et al, KI Reports, Wadei et al, Am J Transpl; contributors added, small changes in numbers in tables; FAQs from Kronbichler et al NDT 2021
April 25: addition of data from Frantzen et al NDT 2021; Rincon-Arevalo et al, MedRxiv 2021; Jahn et al, Vaccines, 2021; 8 week data from Goupil et al; list of contributors
April 27 2021: addition of data from Chavarot et al, Transpl 2021; Yi et al, Transpl 2021; Ou et al, Transpl 2021
June 11 2021: Table on GN after vaccinations
July 28: Third dose studies and large case series on breakthrough infections