Intended for healthcare professionals

Rapid response to:


Will covid-19 vaccines save lives? Current trials aren’t designed to tell us

BMJ 2020; 371 doi: (Published 21 October 2020) Cite this as: BMJ 2020;371:m4037

Linked Editorial

Covid-19 vaccine trial protocols released

Read our latest coverage of the coronavirus outbreak

Rapid Response:

Re: Will covid-19 vaccines save lives? Current trials aren’t designed to tell us

Dear Editor:
Peter Doshi’s nuanced article has opened up a rigorous and valuable discussion about the ongoing COVID-19 mRNA vaccine clinical trials, and I would like to home in on what is perhaps the most salient source of concern about their efficacy and safety, and a key step in building public confidence: the need for extensive data on the vaccines' cellular tropism and MHC Class I vs. MHC Class II-mediated antigen presentation, with attendant questions about potential seeding of autoimmunity. The mRNA vaccines’ nucleic acid payload is ferried into human cells via complex lipid nanoparticles (LNPs) with a lipophilic formulation capable of traversing phospholipid bilayers, through endocytosis and other mechanisms [1]. While some LNP vehicles have been engineered with specific tropisms for target tissues, others have less selective tropisms (or are even potentially omnitropic), capable of entering diverse cell types [2]. From studies thus far, it remains unclear under which category the LNPs used in the COVID vaccine trials appear to fall, and this point is essential for gauging long-term safety and efficacy. If these LNPs have a broad cell tropism, then they would be capable of entering and expressing the SARS-CoV-2 viral spike protein within the parenchyma of vital organs and tissues, well beyond the tropism of wild-type coronavirus. The resulting non-self protein, presented to immune surveillance via MHC-I complexes, would trigger a cytotoxic (CD8-mediated) immune response to the expressing cells, which could with time engender clinically significant tissue damage.

To elaborate briefly on this concern, and the data which could alleviate it, we can roughly subdivide the standard pediatric and adult vaccine repertoires into two broad categories, on the basis of the cells that present the vaccine-mediated antigen to T-lymphocytes. Inactivated virus vaccines (such as Hepatitis A and IPV) and protein subunit vaccines (Hib, Hepatitis B, pertussis) involve primarily MHC-II-based presentation (“Type 1 vaccines” for this discussion). Their antigenic material is taken up principally via phagocytosis by antigen-presenting cells (APCs), particularly dendritic cells in visceral and peripheral tissues, which migrate to lymph nodes and present immunostimulatory epitopes in complex with MHC-II cell-surface molecules to CD4-expressing T-cells (T helper cells), which in turn help to initiate and coordinate the adaptive immune response to pathogens exhibiting the antigen. A cytotoxic response is not induced against the APCs utilizing the MHC-II pathway. Attenuated virus vaccines such as MMR (“Type 2”) enlist not only MHC-II-expressing APCs, but also the MHC-I antigen-presenting pathway present in almost all cell types which, through a standard cascade of events, triggers a cytotoxic response (mediated by CD8-expressing lymphocytes) against presenting cells and tissues, due to the presence of non-self epitopes. Thus attenuated virus (Type 2) vaccines like MMR do entail some cytotoxicity against infected cells, but still confined to the original tropism of the target virus, with an enhanced immunostimulatory effect.

LNP-containing mRNA vaccines represent a novel Type 3 in this classification: enlisting both MHC-II-mediated (through dendritic cells and other APCs) and cytotoxic MHC-I-mediated immunostimulation, but against a far broader array of MHC-I-presenting cells and tissues than the wild-type virus, particularly for LNPs with unselective tissue tropisms. There is potential for enhanced immunostimulatory impact through this process, but also elevated risk of cytotoxic, inflammatory, and autoimmune effects, even more so if the liposomal particles can traverse the blood-brain barrier to enter, for example, motor neurons or oligodendrocytes (the glial cells targeted in multiple sclerosis). These effects, in turn, depend critically on the organ and tissue profile of the cells that receive the LNPs, translate the mRNA payload, and dock the antigenic protein on MHC-I cell-surface molecules. This is doubly true in the case of COVID-19 in light of the still-evolving picture of SARS-CoV-2 immunology. Immune responses appear to be incremental and fleeting, both for natural and vaccine-mediated immunity, suggesting a likely need for multiple boosters after an initial inoculation. Therefore, if cytotoxic responses to integral tissues are transpiring through MHC-I-mediated presentation of SARS-CoV-2 spike protein, the effects may be at first subclinical, manifesting fully only after successive immunizations over months or years.

At present, relatively little has been reported on the tissue localization of the LNPs used to encase the SARS-CoV-2 spike protein-encoding messenger RNA, and it is vital to have more specific information on precisely where the liposomal nanoparticles are going after injection, both in concurrent animal studies and in the two ongoing mRNA vaccine human trials. This process can be commenced in straightforward fashion through cell culture and animal-based investigations, by supplying mRNA expressing a fluorophoric reporter gene (such as green fluorescent protein) delivered via the same LNP formulations as used in the two vaccine trials, and tracking its ingress into varied cells and tissues. The mRNA vaccines represent a remarkable and promising technology, with potential to expedite the development of immunization protocols for future epidemics, but this promise will evaporate if unanticipated safety issues and side effects emerge to weaken public trust in the new modality. Cellular and tissue localization data on the vaccines’ tissue tropisms, obtained and confirmed across multiple independent laboratories, would constitute a valuable step to reinforce public confidence in this regard.

[1] doi: 10.1016/j.addr.2016.04.014. Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier. Ana Beloqui, Anne des Rieux, Véronique Préat. Adv Drug Deliv Rev. 2016 Nov 15;106(Pt B):242-255.
[2] doi: 10.1016/B978-0-12-391860-4.00012-4. Lipid nanoparticles for drug targeting to the brain. Maria Luisa Bondì , Roberto Di Gesù, and Emanuela Fabiola Craparo. Methods Enzymol. 2012;508:229-51.

Competing interests: No competing interests

21 December 2020
JW Ulm
Physician-scientist (MD/PhD)
Los Angeles, CA, USA