Experimental COVID-19 vaccine in combination with adjuvant provides mutation-resistant T cell protection

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The first-generation COVID-19 vaccines have been effective in mitigating severe illness and hospitalization, but recurring waves of infections are associated with the emergence of SARS-CoV-2 variants that display progressive abilities to evade antibodies, leading to diminished vaccine effectiveness.

The lack of clarity on the extent to which vaccine-elicited mucosal or systemic memory T cells protect against such antibody-evasive SARS-CoV-2 variants remains a critical knowledge gap in our quest for broadly protective vaccines.

Using adjuvanted spike protein–based vaccines that elicit potent T cell responses, we assessed whether systemic or lung-resident CD4 and CD8 T cells protected against SARS-CoV-2 variants in the presence or absence of virus-neutralizing antibodies.

We found that:

  • 1) mucosal or parenteral immunization led to effective viral control and protected against lung pathology with or without neutralizing antibodies,
  • 2) protection afforded by mucosal memory CD8 T cells was largely redundant in the presence of antibodies that effectively neutralized the challenge virus, and
  • 3) “unhelped” mucosal memory CD8 T cells provided no protection against the homologous SARS-CoV-2 without CD4 T cells and neutralizing antibodies. Significantly, however, in the absence of detectable virus-neutralizing antibodies, systemic or lung-resident memory CD4 and “helped” CD8 T cells provided effective protection against the relatively antibody-resistant B1.351 (β) variant, without lung immunopathology.

Thus, induction of systemic and mucosal memory T cells directed against conserved epitopes might be an effective strategy to protect against SARS-CoV-2 variants that evade neutralizing antibodies. Mechanistic insights from this work have significant implications in the development of T cell–targeted immunomodulation or broadly protective SARS-CoV-2 vaccines.

Discussion

According to the current axiom, high levels of virus-neutralizing antibodies at portals of viral entry can often confer sterilizing immunity to infections. On the other hand, memory T cells may not provide sterilizing immunity, but curtail viral infections and protect against disease. Hence, it is desirable to develop vaccines that engender both humoral and T cell memory and afford effective protection through two complementary layers

of immunity. With the rapid emergence of highly contagious SARS-CoV-2 variants, such as OMICRON that evade neutralizing antibodies (35–37), there is an urgent need for developing broadly protective vaccines against COVID-19. In this context, there exists a knowledge gap of whether memory T cells can confer immunity to SARS-CoV-2, especially under conditions where virus effectively evades neutralizing antibodies.

In this study, using experimental subunit vaccines, we investigated the tenets of mucosal/resident vs. systemic/migratory T cell immunity in protection against lethal mucosal challenge with the β-variant of SARS-CoV-2 that evades virus-neutralizing antibodies.

Although virus-neutralizing antibodies are front and center to immunity induced by the currently used SARS-CoV-2 vaccines, there is emerging argument that complementary T cell immunity would be paramount for broad protective immunity to newly emerging viral variants (4, 5, 7, 9, 25, 30, 38).

Using the ADJ-based adjuvant system, we questioned whether the tenets of pulmonary T cell immunity to influenza and SARS-CoV-2 are different. Our studies confirmed that mucosal immunization elicited airway/lung TRMs and antibodies in airways, while parenteral immunization induced circulating memory CD4 and CD8 T cells and antibodies. The presence of mucosal or systemic humoral and T cell immunity effectively protects against the homologous Washington strain of SARS-CoV-2; CD4 T cell–dependent immunity (antibodies and CD4 T cells) but not CD8 T cells were nonredundant for vaccine immunity to the Washington strain of SARS-CoV-2.

Notably, in our studies, unhelped memory CD8 T cells in CD4 T cell–depleted mice expanded but failed to protect against the homologous Washington strain of SARS-CoV-2. This finding is consistent with a role for memory CD4 T cells in viral control and in programming protective CD8 T cell memory (39), but incisive studies are warranted to assess whether helped memory CD8 T cells can protect against homologous SARS-CoV-2 challenge, in the absence of neutralizing antibodies and robust CD4 T cell responses.

Most strikingly, even in the absence of detectable virus-neutralizing antibodies in the respiratory tract or serum, mucosal or systemic memory T cells, along with nonneutralizing antibodies, likely conferred effective protective immunity to the South African SARS-CoV-2 β-variant B.1.351.

It should be noted that, unlike a lesser role for vaccine-elicited memory CD8 T cells in vaccine immunity to the Washington strain, vaccine-elicited pulmonary memory CD4 and CD8 T cells play nonredundant roles in mediating protection against the SARS-CoV-2 variant B.1.351. The differences in the contributions of CD8 T cells to protection against the two strains might be linked to the primacy of virus-neutralizing antibodies in protection against the homologous Washington strain but not the B.1.351 variant of SARS-CoV-2.

There is building consensus that T cell-based protective immunity to IAV is mediated by airway and lung TRMs, and our previous work show that only mucosally administered vaccines, but not parenteral vaccines, induce such TRMs and protect against influenza (16–19, 22).

We have also shown that combination nanoemulsion adjuvants containing ADJ and TLR agonists GLA or CpG induced high numbers of lung CD8 and CD4 TRMs and protected against multiple strains of IAV (23). Unlike TRM-centric protection against IAV, either mucosal or parenteral vaccinations protect against the β-variant of SARS-CoV-2, which suggest that both TRMs and systemic migratory memory T cells can protect against SARS-CoV-2.

Likewise, systemic migratory T cell memory controls mucosal challenge with vaccinia virus (40). Taken together, these findings highlight the differences in tenets of T cell–dependent protective immunity to respiratory infections with viruses, such as influenza virus, SARS-CoV-2, and poxvirus, and demonstrate the relative importance of antibodies and T cells in immune prophylaxis against SARS-CoV-2 variants.

Additionally, we found that both memory CD4 and CD8 T cells contribute to protection against the SARS-CoV-2 variant B.1.351, but the exact mechanisms remain unknown. While memory CD8 T cells can mediate viral control by MHC I-restricted cellular cytotoxicity, the role of noncytolytic viral control mechanisms including the production of cytokines, such as IFN-γ or IL-17, cannot be excluded.

Memory CD4 T cells can potentially contribute to viral control directly by producing antiviral cytokines or indirectly by augmenting memory B cell-dependent anamnestic antibody responses (41) or by promoting the activation and trafficking of memory CD8 T cells. However, we did not detect anamnestic neutralizing antibody responses in the serum following challenge with variant B.1.351, nor did we find lower CTL numbers in the lungs of CD4 T cell-depleted virally challenged mice.

Pertaining to the role of T1 vs. T17 immunity in protection, only ADJ+GLA IN vaccine elicited mixed populations of T1 and T17 CD4 and CD8 T cells; ADJ+CpG IN only induced TH17 but not TC17 memory T cells. Regardless of the elicitation of T1 and T17 immunity, we did not observe detectable differences in SARS-CoV-2 control in lungs between vaccines.

However, only in a subset of ADJ+GLA IN mice challenged with β-variant B.1.351 did lungs display severe histological changes, and it will be important to determine whether T17 immunity underlies this lung pathology. In sum, further studies are warranted to understand the mechanisms underlying the memory CD4 and CD8 T cell–dependent control of SARS-CoV-2.

The currently used SARS-CoV-2 mRNA vaccines continue to provide substantive protection against severe disease, despite the emergence of SARS-CoV-2 variants that have grown increasingly resistant to neutralization by vaccine- or infection-elicited antibodies.

In this context, it is noteworthy that SARS-CoV-2 mRNA vaccines induce both antibodies and cross-reactive memory T cells (42, 43). The specific role of memory T cells induced by SARS-CoV-2 mRNA vaccines in protection of humans against SARS-CoV-2 infection and severe disease is unclear. Our studies clearly show that systemic or mucosal memory T cells can mediate effective viral control upon challenge with the relatively antibody-resistant B.1.351 variant of SARS-CoV-2.

Thus, it is possible that cross-reactive memory T cells induced by SARS-CoV-2 mRNA vaccines might protect against severe disease induced by the DELTA and the OMICRON variants.
In this study, using an experimental subunit vaccine consisting of SARS-CoV-2 S protein formulated in a nanoemulsion/TLR agonist-based combination adjuvant administered mucosally or parenterally, we probed the fundamental tenets of T cell immunity to SARS-CoV-2 variants that differ in their abilities to evade antibody-based immunity.

We ascribe key nonredundant roles for lung-resident and systemic migratory memory CD4/CD8 T cells elicited by mucosal or parenteral immunizations, respectively, in limiting lung replication of SARS-CoV-2 variant that evade antibody-based immune defense. These key findings are expected to have significant implications in the development of broadly protective T cell–based vaccines and cellular immunotherapy against COVID-19.

reference link : https://www.pnas.org/doi/full/10.1073/pnas.2118312119

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