Post-adenoviral-based vaccines Guillain-Barre Syndrome: A proposed mechanism.

Despite great public health advances achieved by COVID-19 vaccines, rare side effects may impact the public acceptance. Guillain-Barre Syndrome has increasingly been reported with adenoviral-based vaccines. This perspective proposes a possible mechanism underlying this rare but clinically significant side effect thereby providing insights for improving our current vaccines against COVID-19.

Notwithstanding massive success in reducing the burden of infection and disease achieved by coronavirus disease 2019 (COVID-19) vaccines, concerns regarding their safety still remain. Although exceedingly rare, certain adverse effects can be associated with significant morbidity and mortality smearing this major global public health triumph. There have recently been a number of post adenoviral-based vaccine cases of Guillain-Barre syndrome (GBS) reported in the literature [1], [2], [3], [4] and to regulatory agencies. GBS and its variants have been reported after a range of bacterial and viral infections, Campylobacter jejuni, cytomegalovirus, influenza, Mycoplasma pneumoniae, and flaviviruses such as Zika and dengue viruses among others [2]. GBS has also been repeatedly described shortly after the onset of COVID-19 signs and symptoms [5], [6]. Given the proclivity and association of COVID-19 with GBS and its clinical variants compared with the rarity of post-adenoviral COVID-19 vaccine administration [7], it is inconceivable to reliably attribute causality to the adenoviral vectors used in COVID-19 vaccines; therefore, the search for the smoking gun must continue. Recently, the possibility of molecular mimicry has been investigated in which several SARS-CoV-2 short amino acid sequences showed homology to a range of proteins expressed in the human body [8]. Among several amino acid stretches found within SARS-CoV-2′s spike protein, VYSTGSN heptapeptide near the furin cleavage site, was also found in human neural cell adhesion molecule (NCAM) L1-like protein (aa. 391–397). In addition to the central nervous system, NCAM L1-like protein is also expressed in the peripheral nervous system including in Schwann cells [8]. NCAM L1-like protein has also been proposed to be linked to GBS and COVID-19 [9]. This heptapeptide is predicted to be part of RVYSTGSNVFQ peptide which is a B cell epitope, namely it is recognized by antibodies. Specific or cross-reactive antibodies, therefore, can bind to it and recruit classical complement to the site leading to demyelination and in situ destruction of nerves [10]. This may at least partly explain as to why most, if not all, of these cases have no detectable anti-gangliosides antibodies.

Adenovirus-based COVID-19 vaccines generate pre-fusion trimeric spike proteins that all carry the afore-mentioned peptides. This region is shared, to a great extent, with other common coronaviruses. After infection with SARS-CoV-2, COVID-19 vaccination, or infection with common coronaviruses, strong anamnestic humoral immune responses against the shared epitopes in spike protein are elicited [11]. This may precipitate GBS or GBS-like signs and symptoms as is the case with the reported cases that typically occur within 14 days post-vaccination. The short timeframe post-vaccination within which GBS manifests is reminiscent of the kinetics of an anamnestic immune response. This may particularly be the case in those with a conducive genetic background, HLA-A*68 and HLA-DQA1/HLA-DQB1 haplotypes [9], among others, hence the rarity of this phenomenon. That adenoviruses can trigger stronger innate immune responses such as interferons compared with RNA-bases vaccines, may in turn, stimulate a wide range of cells to up their surface expression of HLA, further setting the stage for a more rigorous immune response.

All in all, this proposed mechanism needs substantiating. Mitigation strategies would include knocking out this peptide region from the vaccines, as long as the tertiary structure of the spike is preserved, so no anamnestic immune response against this epitope arises.

Funding statement

Funding not received for the study

Consent statement/ethical approval

Not required.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.