Third COVID-19 vaccine dose in US cohort of people on immune-suppressing treatment: safety and ethical issues
A US group has reported that using a third dose against COVID-19 can overcome low responses to standard two-dose vaccinations in some people on immune suppressing treatment. 
The study also generated correspondence that included further reports on this approach but also raised ethical issues on vaccine access. It also reported that one participant, a heart transplant recipient, had biopsy-proven antibody-mediated organ rejection, seven days after the third dose. Heart function remained normal without need to increase immune suppressive treatment.
This US cohort included 30 people (17 woman) who had received solid organs transplants who were taking immune suppressive treatment.
Median age was 57 years (IQR: 44 to 62 years), 29 white. In 25 patients, Maintenance immunosuppression included tacrolimus or cyclosporine plus mycophenolate in 25/30, corticosteroids in 2430 with sirolimus and belatacept each used by one person. Median time since the transplant was 4.5 years (IQR: 2.3 to 10.5).
Responses to the first two doses after a median of 67 days (IQR: 54 to 81) had not produced antibody responses in 24/30 and only weak antibody titres in 6/30.
After the third dose, all 6 patients with previously low titres generated high-positive antibody responses. However, in people with no previous response, only 6/24 (25%) generated high responses, 2/24 had low positive titres and 16/24 remained antibody negative.
These results add to positive data reported from a French cohort where overall responses to a third dose increased to 67% in a similar population, without evidence of negative outcomes. 
The individual protection against COVID-19 from a third dose is important given the high risk of serious complications, including fatality, in transplant recipients who develop COVID-19, including after two-dose vaccinations. [3, 4]
The paper also discussed the difficult issue of COVID-19 variants developing in individuals who have extended periods (>6 months) of active infection. This has been reported in transplant recipients, people with cancer and some HIV positive people.
A South African report included breakthrough infections during prolonged COVID-19 with key mutations associated with clinically important variants (including early emergence of the E484K followed by other escape mutations and N501Y). 
This case of viral evolution was in an HIV positive person who had a CD4 count of 6 cells/mm3 and viral load of 35,000 copies/mL despite being on ART (efavirenz/TDF/FTC) before COVID-19 infection. Viral changes in SARS-CoV-2 were tracked in seven whole genome samples.
It is unclear why changing ART was delayed for six months in someone with such advanced HIV and resistance to current ART at baseline. This person was anecdotally receiving very close and supported care that included counselling and support to change, although the paper includes none of these details. 
However, viral load became undetectable (<50 copies/mL) two weeks after switching to TDF/lamivudine/dolutegravir (TLD) at approximately day 200, despite NRTI resistance that included K70KQ and M184V. Other studies showing viral evolution during prolonged COVID-19, where viral pressure have often been complicated by treatment with convalescent plasma or monoclonal antibodies.
This publication by Werbel et al also prompted two important comments.
One was from a second French cohort that only reported overall 30% response to a third vaccine dose in 74 transplant recipients (43% (6/14), 19% (5/26) and 35% (12/34) in liver, kidney and heart recipients, respectively). Independent factors associated with lack of response were more recent transplantations < 2 years (OR: 7.19; 95%CI: 1.17 to 44.28), p= 0.033; and mycophenolic acid-based immunosuppression (OR 9.73; 95%CI: 1.61 to 58.68), p= 0.013. This authors emphasized the important of family members being vaccinated.
The second comment reported cases where people had sought third vaccine doses without involvement of their transplant teams, at a time when vaccine supplies were also limited. It also questioned the ethics of the study by suggesting that written informed consent had not been provided.
These studies raise important issues both for individual and population-based health, all of which urgently need further data.
Firstly, a significant percentage of people with reduced immunity are likely to have suboptimal responses to current two-dose vaccinations. The high risk from COVID-19, reported in several studies, means that caution to avoid infection is still strongly recommended. Management guidelines to ensure optimal care for people in this situation is essential.
Secondly, expanding access to this option of a third dose should be prioritised in the UK, with consent that includes a potential safety risk. This should preferably be in the context of a research setting, and certainly earlier that the Autumn timeline currently proposed by the JCVI. 
This relatively small number of people would not impact on vaccine access given the advanced stage of the UK vaccine programme, and their earlier prioritisation was based on need for effective protection, irrespective of the number of doses.
Thirdly, this shows the importance of developing guidelines for careful management of cases of prolonged COVID-19, to minimise the risk of further transmission, including the potential for complex variants.
- Werbel WA et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series. Ann Int Med, letter. DOI: 10.7326/L21-0282. (15 June 2021).
- Collins S. Third vaccine dose increases immune response to 68% in French transplant recipients. HTB (24 June 2021).
- Kates OS et al. COVID-19 in solid organ transplant: a multi-center cohort study. Clin Infect Dis. 2020. doi:10.1093/cid/ciaa1097. (7 August 2020).
- Ali NM et al. Development of COVID-19 infection in transplant recipients after SARS-CoV-2 vaccination. Transplantation. Letter to editor. 2021. doi:10.1097/TP.0000000000003836. (26 May 2021).
- Karim F et al. Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection. MedRxIV pre-peer review. doi: https://doi.org/10.1101/2021.06.03.21258228. (4 June 2021).
https://www.medrxiv.org/content/10.1101/2021.06.03.21258228v1 (main study)
https://www.medrxiv.org/content/10.1101/2021.06.03.21258228v1.supplementary-material (supplementary material)
- Venter F. Personal communication with leading South African research aware of this case, but not connected to the COVID-19 study reported.
- Collins S. France routinely recommends third dose of COVID-19 vaccine for some people with reduced immune function. HTB (11 May 2021).
This article was first published on 28 June 2021.