Scientists are reporting troubling signs that some recent mutations of the virus that causes COVID-19 may modestly curb the effectiveness of two current vaccines, although they stress that the shots still protect against the disease.
Researchers expressed concern Wednesday about the preliminary findings, in large part because they suggest that future mutations could undermine vaccines. The research tested coronaviruses from the United Kingdom, South Africa and Brazil, and was led by Rockefeller University in New York with scientists from the National Institutes of Health and elsewhere.
A different, more limited study out Wednesday gave encouraging news about one vaccine’s protection against some of the mutations.
One way vaccines work is to prompt the immune system to make antibodies that block the virus from infecting cells. The Rockefeller researchers got blood samples from 20 people who had received either the Moderna or Pfizer vaccine and tested their antibodies against various virus mutations in the lab.
With some, the antibodies didn’t work as well against the virus—activity was one-to-threefold less, depending on the mutation, said the study leader, Rockefeller’s Dr. Michel Nussenzweig.
“It’s a small difference but it is definitely a difference,” he said. The antibody response is “not as good” at blocking the virus.
The latest findings were posted late Tuesday on an online website for researchers and have not yet been published in a journal or reviewed by other scientists. Nussenzweig is paid by the Howard Hughes Medical Institute, which also supports science coverage at The Associated Press. The university has applied for a patent related to his work.
The coronavirus has been growing more genetically diverse, and scientists say the high rate of new cases is the main reason. Each new infection gives the virus a chance to mutate as it makes copies of itself.
Recent variants, or versions of the virus that emerged in the U.K., South Africa and Brazil seem to spread more easily and scientists say that will lead to more cases, deaths and hospitalizations. The new variants do not seem to cause more serious disease but their ability to eventually undercut vaccines is a concern.
E. John Wherry, an immunology expert at the University of Pennsylvania, said the Rockefeller scientists are “among the very best in the world” at this work and their results are concerning.
“We don’t want people thinking that the current vaccine is already outdated. That’s absolutely not true,” he said. “There’s still immunity here … a good level of protection,” but the mutations “do in fact reduce how well our immune response is recognizing the virus.”
The news comes at “a really important time in the pandemic,” said Dr. Buddy Creech, a vaccine specialist at Vanderbilt University,
“We’ve got an arms race between the vaccines and the virus. The slower we roll out vaccine around the world, the more opportunities we give this virus to escape” and develop mutations, he said.
Dr. Matthew Woodruff, an immunology researcher at Emory University, agreed.
“This is going to be kind of a slow walk of evolution. We’re going to have to have tools that slowly develop with it,” such as treatments that offer combinations of antibodies rather than one, he said.
Dr. Drew Weissman, a University of Pennsylvania scientist whose work helped lead to the Moderna and Pfizer vaccines, said the antibody findings are worrisome, but noted that vaccines also protect in other ways, such as spurring responses from other parts of the immune system.
The new work involved only 20 people and not a huge range of ages or races, “and all of that matters” in how generalizable the results are, he said.
On Wednesday, Pfizer and its German partner BioNTech reported a second round of reassuring findings about its vaccine against one of the variants.
Earlier this month, Pfizer and researchers at the University of Texas Medical Branch said that the vaccine remained effective against a mutation called N501Y from new variants found in the U.K. and South Africa. Likewise, there was no sign of trouble when they tested some additional mutations.
The latest work tested all the mutations from the variant from the U.K. at once rather than one-by-one. Tests from 16 vaccine recipients showed no big difference in the ability of antibodies to block the virus, the researchers said in a report.
Pfizer didn’t immediately comment about the Rockefeller findings, but its chief scientific officer, Dr. Philip Dormitzer, previously said next steps include testing the vaccine against additional mutations found in the variant from South Africa.
Moderna and AstraZeneca, which makes a different type of COVID-19 vaccine used in some countries, also have been testing how their vaccines hold up against different mutations.
If the virus eventually mutates enough that the vaccine needs adjusting—much like flu shots are altered most years – tweaking the recipe wouldn’t be difficult for vaccines made with newer technologies. Both the Pfizer and Moderna vaccines are made with a piece of the virus genetic code that is simple to switch.
It’s “wishful thinking” to believe that first-generation vaccines will be enough, or that vaccines alone will solve our problems, said Mayo Clinic vaccine expert Dr. Gregory Poland.
“We are shooting ourselves in the foot by allowing unmitigated transmission of this virus” and not doing “common sense” measures such as mandating mask-wearing as some other countries are doing, he said.
“How can the bars and restaurants be full? It’s like ‘what pandemic?’ We’ve reaped the seeds we’ve sown,” he said.
Immunity and immunopathology
In order to understand the mechanisms by which the immune system, upon the SARS-CoV-2 recognition, can mount efficient immune responses, it is important to know SARS-CoV-2 tropism and dynamics. The S glycoprotein of SARS-CoV-2 binds hACE2 with significantly higher affinity than SARS-CoV S, and in concert with the host transmembrane serine protease 2 (TMPRSS2) and other host proteases [10, 12], mediates cellular entry. Recently, human, non-human primate, and mouse single-cell RNA-sequencing datasets showed that ACE2 and TMPRSS2 are particularly expressed in lung type II pneumocytes, ileal absorptive enterocytes, nasal goblet secretory cells, and corneal cells [13, 14], supporting the clinical pictures that are more commonly correlated with COVID-19 infection. Importantly, ACE2 gene was proposed as an interferon-stimulating gene (ISG), suggesting that the resulting production of type I IFNs upregulates ACE2 expression .
Tissue-resident macrophages, dendritic cells (DCs), and neutrophils expressing a wide range of pattern-recognition receptors (PRRs), upon the engagement with various damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) (i.e., the single-stranded SARS-CoV-2 RNA binding the endosomal TLRs 7 or 8)  induce the activation of distinct signaling pathways promoting production of type I and Type III IFNs , as well as of IL-1β and IL-6 promoting recruitment of neutrophils and CD8+ T cells, or protective antibody production  (Fig. 1).
Activated DCs normally patrolling tissues acquire high capacity to phagocytose dying or apoptotic cells (e.g., infected by SARS-CoV-2), upregulate chemokine receptors that guide their migration into draining lymph nodes, and prime virus-specific naive B or T cells to proliferate and differentiate into plasma cells producing anti-viral antibodies and various effector T cell populations, respectively.
Effector CD4+ and CD8+ T cells can then retro-migrate into inflamed tissue to fight the virus through the production of antiviral cytokines suppressing viral replication (e.g., by IFN-γ production), and the antigen-specific killing of infected cells (by CD8+ T cells)  (Fig. (Fig.1).1).
Tissues like respiratory tract or gut contain a large amount of secondary mucosal-associated lymphoid tissues (MALTs) that can contribute to the generation of tissue-resident memory T cells (TRMs) [19–23]. In this context, various natural killer (NK) cell and innate lymphoid cell (ILC) populations expressing a wide repertoire of activating receptors (Rs) and inflammatory cytokines, may play a key role in sustaining tissue inflammation and killing virus-infected cells (upregulating various NKR ligands) in situ [24, 25] (Fig. (Fig.1).1).
In addition, MALT-associated invariant NKT cells, γδT cells, or B cell follicles [26–28] need to be taken in consideration in SARS-CoV-2 infection. Whether these immune responses result protective or harmful in COVID-19 infection, it likely depends on whether they are generated in individuals with the genetic and immunological features, more or less reactive to respond promptly or late (Fig. (Fig.1).1).
In general, the majority of patients infected with SARS-CoVs develop a multistep cascade leading to efficient immune responses, and ultimately to the recovery. Recent studies showed a high level of SARS-CoV-2-specific CD4+ and CD8+ T cell activation and expansion in the majority of patients (~ 70–100%) recovering from COVID-19 infection or patients with active infection, consistent with an effective adaptive immune response against several viral epitopes from various proteins (S, M, N, nsps, ORFs…).
Interestingly, SARS-CoV-2-reactive CD4+ T cells were detected in PBMCs collected several years before the pandemic, in a high percentage of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2. Further studied are demanded to ascertain if these responses are effectively protective, correlate with positive outcomes, and provide long-term memory.
Several molecular, cellular, experimental and clinical immunology studies indicate that the majority of effector B or T lymphocytes disappear after pathogen eradication, through the serial intervention of multiple immunoregulatory mechanisms, including those mediated by immune checkpoints (e.g., PD-1 or CTLA-4 interacting with their correspondent ligands [PD-L1 or B7.1 / B7.2] , or by Tregs [30, 31], in order to avoid useless damages to the host tissues and organs (Fig. (Fig.1).1).
The stop signals provided by immune checkpoints also contribute to develop immunological memory by the conversion of a minority of effector cells into memory B or T cells, through the adaption of several molecular and epigenetic mechanisms [32–37]. Memory lymphocytes remain quiescent in lymphatic tissues or peripheral tissues, but, once they meet again the primary pathogen, they are promptly activated (avoiding the priming period that characterizes a primary infection), neutralize the pathogen, without any disease, and can maintain a lasting and protective immunological memory for several years (long-term memory): this is the principle of vaccinations.
The problem is if the immunological memory lasts a few months. Short-term immunological memory occurs when the virus evades the immune responses (e.g., viral persistence), and/or when concurrent causes such as the immune senescence  and various co-morbidities (metabolic syndrome, severe generalized immunodeficiencies, tumors, cirrhosis, abuse of alcohol, tobacco or other substances) raise. This leads to recurrent susceptibility to the viral pathogen.
Whether SARS-CoV-2 recalls a long-term immunological memory, similarly to the SARS-CoV (which was however significantly more lethal than SARS-CoV-2), or short term immunological memory, such as other members of the CoVs family, the HCoV-OC43 and HCoV-HKU1 (the second most important causes of common cold), which in winter seasons affects individuals regardless exposures in previous years , is a current matter of investigation.
The months ahead will be crucial to determine the immunological memory of SARS-CoV-2 by monitoring subjects recovered from a primary COVID-19 . Short-term memory could also convert into long-term memory by the exposure to repeated viral “boosts”, but this remains a pure hypothesis at the moment.
Another important aspect related to the immune response against SARS-CoV-2 is that the CoVs (including SARS-CoV and MERS-CoV) are unique RNA viruses with a genomic proofreading mechanism, that limits the accumulation of mutations [39–41]. This would make these viruses refractory to easy immunosurveillance escape. However, the evidence that the different CoVs frequently recombine their RNA among themselves, suggests that they can undergo a certain degree of variability and capacity of viral escape by this recombination mechanism, in the unluckily scenario that more types of CoVs infect the same cell .
Whether SARS-CoVs display their pathogenicity through direct cytolytic or indirect non-cytolytic mechanisms, or both, is not completely clarified. The previous SARS-CoV infection in humans caused an atypical pneumonia with a 10% fatality rate, and (in analogy with CoVs of other animals) could induce viral persistence, T cell lymphopenia, and severe disease for several months. This spectrum resembles at least in part the clinical and viral aspects observed in the severe form of COVID-19.
The evidence that SARS-CoV-2 can cause different clinical outcomes from asymptomatic to severe symptomatic infection range, leads to hypothesize that it is a poor cytopathic virus, and cell damage is not due to a direct viral effect, but rather by the immune responses elicited to eliminate the virus-infected cells by various effector mechanisms, including killing by CD8+ T cells and NK cells, PRR-dependent activation of pro-inflammatory cells (e.g., macrophages, neutrophils…), antiviral and inflammatory cytokines produced by NK cells, NKT cells, ILCs, CD4+ and CD8+ T cells, TRM cells .
Therefore, viral clearance depends on appropriate level of immunopathology that helps production of neutralizing high affinity antibodies by plasma cells [11, 17], and causes recovery in the majority of infected individuals. More in-depth studies on innate and adaptive immunity, during the various phases of the infection, are needed to understand how some patients display an asymptomatic COVID-19, while others a mild or severe symptomatic disease, which can evolve towards the recovery in the majority of them, or the death in a certain fraction. It will be important to understand the checkpoints affected by the virus to overcome the immune system and establish a more or less severe disease that, in the more severe forms, can persist up to more than 2 months.
The diversified clinical outcome of infections is caused by a multifactorial process, to which can contribute and intersect genetic, immune, virus-dependent factors. The most important host genetic factor is represented by the polymorphism of MHC alleles, whose principal function is the presentation of the immunogenic peptides to TCRs on T cells. This MHC capacity likely provides the most reasonable explanation of the relative risk of disease (including autoimmune diseases and infections) in individuals with particular MHC haplotypes [43, 44].
Therefore, it will be critical to study if particular class I and class II alleles are associated with the development of protective immune responses to SARS-CoV-2 or with disease progression (asymptomatic or symptomatic). However, the MHC allele association will represent only a piece of the mosaic that constitutes the multifactorialilty underlying the infection outcome. In addition, genome wide association studies are required to define non-MHC genes associated with COVID-19, including polymorphisms of innate sensor receptors such as NOD-like, or interleukin receptors, despite it is very difficult to define their pathogenic pathways.
SARS-CoV-2 may directly antagonize (by their own viral proteins) the first cellular antiviral defense mediated by the transcriptional induction of Type I and III IFN and the subsequent ISGs, as well as demonstrated for SARS-CoV . This hypothesis is consistent with the recent report indicating that the initial host response to SARS-CoV-2 fails to produce efficient type I and type III responses, but induces high levels of a wide array of chemokines recruiting effector cells, including neutrophils as well as adaptive immune cells  (Fig. 2).
This imbalance would result in the incapacity to promptly stop viral replication, on one hand, and in the maintenance of the inflammatory cascade that is correlated with different levels of disease severity, on other hand. Cytokines, such as IL-1β and IL-6 that are largely secreted by macrophages, as well as a plethora of other inflammatory cytokines including IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, and TNF are directly correlated with the COVID-19 severity  (Fig. (Fig.2).2).
This cytokine storm may cause various organ failures including principally the lung and then hearth, liver and kidney, to which contribute the triggering of the coagulatory cascade, generating clots and thrombosis in multiple tissues and organs. The pulmonary impairment is due to the extensive pneumonia, characterized by diffuse alveolar damage with wide infiltration of neutrophils, macrophages, NK cells, activated T cells.
The massive compartmentalization of innate and adaptive immune cells in the inflamed tissues may explain the severe peripheral lymphopenia with decreased numbers of CD4+ T cells, CD8+ T cells, NK cells, and B cells that is correlated with high levels of viral load in severe COVID-19 [47, 48]). NK cells showed lower percentages of CD107a, IFN-γ, IL-2, TNF-α and granzyme B than those in healthy donors in COVID-19 patients [49, 50]. Lung-infiltrating T cells are in particular constituted by terminally effector T cells upregulating different levels of molecules and genes associated with both T cell activation and exhaustion (PD-1, TIM-3, etc)  (Fig. (Fig.22).
The tissue T cells (likely including the virus-specific) can acquire various functional phenotypes (type-1, type-2, type-17), according to the organ in which they emerge (lung or gut, in particular), and will result protective or detrimental according to disease stage. They may express a partial exhausted phenotype that spontaneously restores into a functional phenotype efficiently limiting or clearing virus replication (recovery) in the mild infection, whereas they progress towards a fully exhausted/dysfunctional phenotype that is generally associated with immunopathology but not with protection, in the severe infection [52, 53].
These two divergent immunological outcomes are epigenetically dictated according to the duration of viral infection and the stimulation strength of virus-specific T cells [54, 55]. Moreover, NK cells were phenotypically exhausted in COVID-19 patients, due to the increased expression of NKG2A , an inhibitory receptor able to induce NK cell exhaustion in chronic viral infections .
Contextually, further studies are required for ascertaining if the T cell responses against several viral epitopes found in the majority of patients with active infection, result dysfunctional (because exhausted), where they may contribute to maintain the immuno-inflammation, as is the case in chronic (e.g., HBV, HCV) infections .
Consistent with this hypothesis, it has been recently proposed that symptomatic COVID-19 behaves more as a subacute rather than an acute disease and may be related with the inability to promptly clear the virus and establish a transient viral persistence . This hypothesis is based on the evidence that SARS-CoV-2 can show a longer median incubation time, a longer disease progression and lymphopenia compared with patients with acute infection, such as influenza , and that symptomatic forms of various human SARS-CoV infections can induce viral persistence and T cell lymphopenia.
A further aspect to consider is the constitutive immunological homeostasis regulating the immune responses in frontline organs, such as the respiratory or gut tracts that are continuously exposed to external antigens [19–23]. The maintenance of the local mucosal immunoregulation is mandatory to guarantee the integrity of mucosal tissues and to avoid disastrous chronic inflammations, by limiting immune responses against highly immunogenic microbiota, external pathogens, diet products, or plants. Indeed, these districts are equipped by a very large vascular bed (recruiting neutrophils and memory T cells), and an equally large surface area of MALT (containing B cells producing secretory IgA, macrophages, various types of DCs, intraepithelial T cells, TRMs…) [19, 20, 22, 23].
The mucosal immunoregulation is principally caused by the presence of various types of local Treg subsets suppressing by various mechanisms (CTLA-4–, TGF-β-, IL-10-dependent…), harmful type-1, type-2, type-17, type-22 immune responses that are generated according to innate immune microenvironments of the different districts [32, 59] (Fig. (Fig.2).2). It would be important to investigate the role of Tregs in the various phases of COVID-19 infection.
Therefore, the mucosal immunoregulation may consistently contribute to establish a status of prolonged mild-level inflammation in severe COVID-19 infection, in order to avoid excessive tissue damage, on one hand, and the complete suppression of antiviral responses, on the other hand. This scenario is close to the chronic low-level inflammation status occurring in chronic infections, with the main difference that the former is self-limited and runs out when infection finishes, while the latter chronically persists in relation with the viral persistence, for decades and often until death in a remarkable number of patients .
This hypothesis is consistent with the observation that the cytokine storm occurring in severe COVID-19 infection is never configured as the so-called “cytokine release syndrome” (CRS) observed in patients with endotoxemia or treated with chimeric antigen receptor-transduced T cells (CAR-T): in these settings, CRS is hyper-acute, shows several fold higher levels of cytokines, neurotoxicity, hypotension and shock, and is significantly more deadly .
In this context, a critical phenomenon that may strongly contribute to the intermediate form of CRS observed in severe COVID-19 infection, is the so-called “by-stander immune activation” (BIA), due to (non-virus-specific) T cell responses that contribute to immunopathology during viral infections or various inflammatory diseases [60–63]. BIA can be sustained by several mechanisms [60, 61, 63, 64], including cryptic self-antigens unveiled during the apoptotic T cell turn-over [65, 66] (Fig. (Fig.2).2).
Indeed, activated T cells undergoing apoptosis can activate DCs by the interaction between CD40 ligand expressed by (activated) apoptotic T cells and CD40 expressed by DCs [67–69]. The so-activated DCs can then phagocytose apoptotic T cells, process caspase-cleaved structural cellular proteins such as myosin, vimentin, and actin, and cross-present the resulting apoptosis-associated epitopes (AEs) to autoreactive CD8+ T cells .
In turn, the latter undergo apoptosis, upon performing their effector functions, maintaining a vicious circle responsible for the amplification of BIA in various (viral or non-viral) forms of acute or chronic inflammatory diseases [65, 70–73]. Because of the enormous accumulation of activated T cells undergoing apoptosis in the various inflamed districts involved in symptomatic COVID-19 infection, further investigations need to determine if AE-specific T cells may sustain BIA in this infection and correlate with the disease progression (Fig. (Fig.2).2). Among other things, this review can pave the way for setting up novel therapeutic approaches addressed to switch off BIA.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769684/