Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity?

Abstract

Many nations are pursuing the rollout of SARS-CoV-2 vaccines as an exit strategy from unprecedented COVID-19-related restrictions. However, the success of this strategy relies critically on the duration of protective immunity resulting from both natural infection and vaccination. SARS-CoV-2 infection elicits an adaptive immune response against a large breadth of viral epitopes, although the duration of the response varies with age and disease severity. Current evidence from case studies and large observational studies suggests that, consistent with research on other common respiratory viruses, a protective immunological response lasts for approximately 5-12 months from primary infection, with reinfection being more likely given an insufficiently robust primary humoral response. Markers of humoral and cell-mediated immune memory can persist over many months, and might help to mitigate against severe disease upon reinfection. Emerging data, including evidence of breakthrough infections, suggest that vaccine effectiveness might be reduced significantly against emerging variants of concern, and hence secondary vaccines will need to be developed to maintain population-level protective immunity. Nonetheless, other interventions will also be required, with further outbreaks likely to occur due to antigenic drift, selective pressures for novel variants, and global population mobility.

Figure 1

Molecular mechanisms of innate immune activation after SARS-CoV-2 infection SARS-CoV-2 enters host cells via interactions between the surface unit S1 of the S protein and host ACE2 and TMPRSS2, followed by endocytosis and viral genome release into the cytosol. Intermediate double-stranded RNA forms, present during viral replication, are recognised as PAMPs by various cytosolic host PRRs, including MDA5, LGP2, and NOD1. These PRRs signal through MAVS to activate a plethora of downstream components, in turn causing activation of IKKε and TBK1. These kinases phosphorylate IRF3, which dimerises and translocates to the nucleus where it activates various transcription factors (NF-κB, IRF3, IRF5) to induce transcription of genes encoding type I interferons., , The host cell also has type I interferon receptors with extracellular domains that bind type I interferons, leading to a molecular cascade via the JAK–STAT pathway that culminates in the binding of the STAT1–STAT2–IRF9 heterodimer to the ISRE and the stimulation of ISGs, which exert various antiviral effects. SARS-CoV-2 can evade the antiviral effects of type I interferons by various molecular mechanisms. For example, nsp13 blocks phosphorylation of TBK1 and hence activation of IRF3, and various nsps and ORFs prevent phosphorylation of STAT1 and STAT2, in turn preventing the formation of the interferon-stimulated gene factor (ie, the STAT1–STAT2 heterodimer bound to IRF9). ORF6 also binds importin and blocks nuclear translocation of both STAT1 and IRF3, downregulating expression of ISGs and production of interferons. ACE2=angiotensin-converting enzyme 2. IKKε=inhibitor of κ-B kinase ε. IRF=interferon regulatory factor. ISGs=interferon-stimulated genes. ISRE=interferon-stimulated regulatory element. JAK=Janus kinase. LGP2=laboratory of genetics and physiology 2. MAVS=mitochondrial antiviral-signalling protein. MDA5=melanoma differentiation-associated protein 5. NF-κB=nuclear factor kappa-light-chain-enhancer of activated B cells. NOD1=nucleotide-binding oligomerisation domain containing 1. nsp=non-structural protein. ORF=open reading frame. P=phosphorylation. PAMPs=pathogen-associated molecular patterns. PRRs=pattern recognition receptors. S=spike. STAT=signal transducer and activator of transcription. TBK1=TANK-binding kinase 1. TMPRSS2=transmembrane protease serine 2.

Figure 2

Overview of the adaptive immune response to SARS-CoV-2 The detection of viral RNA in infected epithelial cells leads to the production of interferons and proinflammatory cytokines. Dendritic cells recognise the presence of PAMPs (eg, viral RNA) and inflammatory markers (eg, interferons), leading to their activation. Activated dendritic cells migrate to lymph nodes and present antigen (on MHC class I or class II molecules) and co-stimulatory molecules to immature T cells, which differentiate into CD8⁺ cytotoxic T lymphocytes, CD4⁺ T cells, or Tfh cells (all of which can differentiate into long-term memory cells). Tfh cells interact with and activate B cells, which differentiate into plasma cells (which produce high-affinity antibodies to specific viral antigens) or memory B cells. Viral antigens processed in phagolysosomes of infected epithelial cells are presented on the cell surface via MHC molecules. Peripherally circulating cytotoxic T lymphocytes recognise antigen-containing MHC class I molecules via their CD8 co-receptors, and interactions between CD8–T-cell co-receptors and MHC class I molecules activate cytotoxic T lymphocytes, leading to the release of proinflammatory cytokines and cytotoxic granules such as granzymes, which trigger apoptosis of the infected host cell. However, SARS-CoV-2 can hinder the adaptive immune response; the accessory protein ORF8 localises in lysosomes and downregulates trafficking of MHC class I molecules to the surface of epithelial cells, thereby reducing cytotoxic-T-lymphocyte-mediated killing of infected cells and downstream immune activation., , dsRNA=double-stranded RNA. ISGs=interferon-stimulated genes. ORF8=open reading frame 8. PAMPs=pathogen-associated molecular patterns. Tfh=T follicular helper.

Figure 3

Associations between PCR test positivity and number of days since symptom onset for swabs taken in the upper respiratory tract and other locations The raw data, with uncertainties (the narrowest 68% interval in the beta distribution implied by the number of positives and number of negatives on a particular day), are plotted and an exponential fit is shown. The data show that it is possible to test positive more than 6 weeks after symptom onset, especially when the specimen is taken from locations other than the upper respiratory tract (eg, blood or faeces). Data were extracted from a published systematic review of individual data.