T cell-mediated immune response to respiratory coronaviruses and vaccines against SARS-CoV that induce immunopathology.

N-protein of SARS-CoV-1 can elicit T cell response in humans.

Channappanavar et al. (Stanley Perlman group), 2014 (1):

Since the S protein of SARS-CoV is capable of inducing
neutralizing antibodies, CD4 and CD8 T responses and N
protein can elicit T cell response in humans, both of these
proteins are useful potential vaccine candidates able to
generate a strong humoral and cell-mediated immune
response against SARS-CoV.

“One caveat is that immunizations with some vaccines encoding the N protein induce an eosinophilic response (Bolles, 2011 (2)), so these vaccines will need to be monitored carefully.” – Channappanavar et al., 2014 (1).

Multiple challenges they encountered with vaccines against SARS-CoV-1 targeting N protein in mice.

Below, there is the abstract of the paper by Bolles et al., 2011 (2), that describes multiple challenges they encountered with vaccines against SARS-CoV-1 targeting N protein in mice. In older mice, the immune response was reduced, the protection against infection was weak and there was eosinophilic immune pathology after vaccines administration. Bolles et al. (Ralph Baric group), 2011 (2):

Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.

Senescent immune system provides challenges for immunisation.

Senescent immune system provides challenges for immunisation also in humans. We discussed this in another article on this website:

COVID-19 vaccines are unlikely to protect those who are at a higher risk. A 2006 study: Vaccines fail to generate protective immunity in 50% to 90% of older individuals.

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rDNA vaccines against SARS-CoV-1 induced specific memory CD4 and CD8 T cells, but very few studies have demonstrated their in vivo potential to clear virus.

In the following citation, other challanges with vaccines against SARS-CoV-1 are discussed, in particular, challenges related to rDNA vaccine. We should also note that injecting foreign DNA in humans is not banal. In a sense, humans injected with foreign DNA can be considered a “new species”. Channappanavar et al. (Stanley Perlman group), 2014 (1):

Immunization of mice with rDNA vaccine encoding the S, N, M or E protein of SARS-CoV induced virus-specific memory CD4 and CD8 T cells [63, 102, 103]. Virus-specific memory CD4 and CD8 T cells were able to produce effector cytokines (e.g., IFN-c) and cytolytic molecules upon in vitro peptide stimulation [102]. Although several groups demonstrated the presence of SARS-CoV-specific memory CD4 and CD8 T cells, very few studies have demonstrated their in vivo potential to clear virus.

“Despite the lack of virus-specific memory B cell response, SARS-CoV- specific memory T cells persist in SARS-recovered patients for up to 6 years.”

“T cell response would provide robust long-term memory.”

The following citation provides an insight on what is a good vaccine as well as a piece of Physiological Literacy on different types of immune response, B cell mediated and T cell mediated. Channappanavar et al. (Stanley Perlman group), 2014 (1):

Despite the lack of virus-specific memory B cell response, SARS-CoV- specific memory T cells persist in SARS-recovered patients for up to 6 years post-infection. Consistent with these human studies, results from animal studies also suggest that strong virus-specific T cell response are required to protect mice from lethal SARS-CoV-MA15 infection. The future vaccine interventions should also consider strategies to enhance T cell response to provide robust long-term memory. Since, tissue-resident memory T cells provide better protection, boosting a local and systemic memory T cell response would be a useful strategy than either of these interventions alone.

Selected references:

1. Rudragouda Channappanavar• Jincun Zhao• Stanley Perlman, Immunol Res (2014) 59:118–128.

2. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, Funkhouser W, Gralinski L, Totura A, Heise M, Baric RS. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011;85:12201–15.