Johnson & Johnson COVID-19 Vaccine Prevents SARS-CoV-2-Induced Thrombosis And Inflammation


A new study by researchers from Beth Israel Deaconess Medical Center-Boston-US, University of Montreal-Canada, M Tufts University-Massachusetts-USA, Oregon Health & Sciences University-USA, Ragon Institute of MGH, MIT, and Harvard-USA has found that the Johnson & Johnson COVID-19 vaccine Ad26.COV2.S not only prevents SARS-CoV-2 induced thrombosis but also prevents virus-induced inflammation besides being able to produce antibodies that neutralize the novel coronavirus.

Although the studies were conducted in hamster models, the study findings show that the Johnson and Johnson COVID-19 vaccine is not only an effective vaccine but also can be considered as one of the most safest vaccine.

The study findings showed that vaccination with Ad26.COV2.S protected SARS-CoV-2 challenged hamsters from developing severe COVID-19 disease by attenuating excessive proinflammatory responses, such as IL-6 and IL-1, macrophages and neutrophils signaling.

Ad26 vaccination also prevented the upregulation of pathways associated with thrombosis such coagulation and clotting cascades associated with infection, and the transcriptomic profiles of vaccinated animals were largely comparable to control uninfected hamsters.

In contrast, SARS-CoV-2 challenged unvaccinated hamsters showed significant increase of these proinflammatory and prothrombotic pathways and significant weight loss compared to vaccinated hamsters.

The study findings were published on a preprint server and are currently being peer reviewed.

Golden Syrian hamsters show productive viral replication, lung pathology, and mortality when challenged with SARS-CoV2 (3, 6-8), making them pertinent for vaccine evaluation. Reports of transcriptomics and proteomics profiling of blood and lung tissues from hamsters infected with SARS-CoV-2 have shown significant upregulation of interferon and proinflammatory pathways, activation of the complement system, and recruitment of neutrophils and macrophages to the lung of infected hamsters that correlates with the presence of SARS-CoV-2 viral RNA (6, 9), supporting the role of these pro-inflammatory responses in COVID-19 severity (10).

Therefore, it is important to test whether vaccines developed against COVID-19 modulate the host immune and transcriptional responses and protect from excessive proinflammatory responses induced by SARS-CoV-2.

We recently demonstrated that a single immunization with Ad26.COV2.S, an adenovirus serotype 26 (Ad26) vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein, elicited binding and neutralizing antibody (NAb) responses and protected hamsters against SARS-CoV-2-induced weight loss, pneumonia, and mortality (3).

These preclinical data stimulated clinical trials that demonstrated immunogenicity and efficacy of Ad26.COV2.S in humans (11, 12).

In this study we performed in depth analyses of bulk RNA-Seq transcriptomic profiling of lung tissues at day 4 post SARS-CoV-2 challenge from Ad26.COV2.S vaccinated and sham unvaccinated hamsters. To characterize Ad26 vaccine-mediated protection from severe COVID-19 in hamsters, we integrated the transcriptomics data with virological data as well as adaptive immune responses elicited by Ad26 at weeks 2 and 4.

We show that a single immunization with Ad26.COV2.S (also termed Ad26.S.PP) attenuated the upregulation of proinflammatory pathways and prevented the upregulation of thrombosis associated pathways such as platelet aggregation, blood coagulation and the clotting cascade.

We also find that Ad26.COV2.S vaccination upregulated signatures of CD4+, CD8+, and B cell responses that correlated with the magnitude of Ad26-elicited humoral immune responses weeks following immunization. Together, these results provide new insights into the molecular and the immunological mechanisms of Ad26.COV2.S protection from severe COVID-19.

The Ad26.COV2.S vaccine comprises a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector7 encoding a full-length, membrane-bound SARS-CoV-2 spike protein in a prefusion-stabilized conformation.8,9

Other Ad26-based vaccines, including an approved Ebola vaccine, are safe and have induced durable immune responses.8,10-13

Ad26.COV2.S induced durable protection at low doses in preclinical SARS-CoV-2 challenge studies,8,14 and initial clinical data showed that a single dose at 5×1010 viral particles was safe and induced excellent humoral and cellular immune responses.9 Ad26.COV2.S can be stored for up to 2 years in a standard freezer and up to 3 months at refrigerator temperatures, which simplifies transport, storage, and use in a pandemic.

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SARS-CoV-2 variants have emerged with several mutations in targets of neutralizing antibodies, such as the E484K mutation. Median pseudovirus neutralizing antibody titres induced by Ad26.COV2.S were 5.0-fold lower against the B.1.351 variant and 3.3-fold lower against the P.1 variant as compared with the original WA1/2020 strain, which is a comparable reduction of psVNA titres that has been reported for other vaccines4,6,7. By contrast, functional non-neutralizing antibody responses and CD8+ and CD4+ T cell responses were largely preserved against SARS-CoV-2 variants of concern.

In the phase III ENSEMBLE trial1, Ad26.COV2.S was evaluated in the USA, Latin America including Brazil, and South Africa. In South Africa, 95% of sequenced viruses from COVID-19 cases were of the B.1.351 variant, and in Brazil, 69% of sequenced viruses from COVID-19 cases were of the P.2 lineage. Protective efficacy of Ad26.COV2.S against severe or critical disease was similar in all geographic locations by day 28, and protective efficacy against moderate to severe disease was only slightly reduced in South Africa compared with the USA.

Although the mechanistic correlates of protection for COVID-19 are not yet known, the robust protective efficacy in these regions despite reduced neutralizing antibodies raises the possibility that functional non-neutralizing antibodies and/or CD8+ T cell responses may also contribute to protection.

Indeed, TCRβ sequencing revealed substantial breadth of T cell responses in individuals vaccinated with Ad26.COV2.S. Alternatively, it is possible that low levels of neutralizing antibodies are sufficient for protection. In a non-human primate model, adoptive transfer of purified IgG was sufficient for protection against SARS-CoV-2 if titres of psVNA exceeded a threshold of approximately 50, but CD8+ T cells also contributed to protection if antibody titres were subprotective22,23.

In conclusion, neutralizing antibody responses elicited by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but other functional antibody responses and T cell responses were largely preserved against these variants. The relevance of these immune parameters to mechanistic correlates of vaccine efficacy remains to be determined.

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