Immunity to COVID-19

SARS-CoV-2 origin and transmission

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first identified in December 2019, is the etiological agent of coronavirus disease (COVID-19).
SARS-CoV-2 has zoonotic origin, and shares genomic similarity with other zoonotic viruses responsible for SARS (SARS-CoV-1) and MERS (EMC/2012 coronavirus)
Genomic analysis SARS-CoV-2 has demonstrated that the virus has a receptor binding domain in the spike (S) protein consisting of 6 amino acids which not only differentiates it from SARS-CoV-1 but also confers it with ability to bind human or human-like Angiotensin Converting Enzyme-1 (ACE2) with high affinity.
SARS-CoV-2 also has a polybasic furin cleavage site on the highly variable spike protein which is also unique to SARS-CoV-2. This site allows cleavage by proteases and determines viral host range and is potentially associated with increased transmission of SARS-CoV-2 in humans.
SARS-CoV-2 is airborne, thus wearing a mask remains one of the most effective precautionary measures for preventing acquisition of the virus (Figure 1).

Figure 1: Phases involved in airborne transmission of respiratory viruses: Virus-laden aerosols (<100 I1/4m) are first generated by an infected individual through expiratory activities, through which they are exhaled and transported in the environment. They may be inhaled by a potential host to initiate a new infection, provided that they remain infectious. In contrast to droplets (>100 I1/4m), aerosols can linger in air for hours and travel beyond 1 to 2 m from the infected individual who exhales them, causing new infections at both short and long ranges. CREDIT: N. CARY/SCIENCE [Source: Wang et al., 2021]

SARS-COV-2 Pathogenesis

SARS-CoV-2 causes a broad spectrum diseases ranging from asymptomatic infection to severe symptomatic disuses (Figure 2). Most individuals infected with SARS-CoV-2 are asymptomatic or develop mild symptoms such as fever, cough, malaise, myalgia, headache, and taste and smell disturbance.
Severe COVID-19 is associated with excessive innate immunity which results in pathology leading to more host cell and tissue damage even when viral load is low. Additionally, individuals with severe COVID-19 also develop additional complications such as thrombosis, sepsis and multi-organ dysfunction.
Infection induces robust antibody (Ab) and T cell responses, which in most cases likely controls viremia before COVID-19 pathogenesis progressors.
Studies have shown that although circulating SARS-CoV-2-specific Ab and T cell responses may wane quickly, natural infection (and potentially vaccination) induces long-lasting memory B cell immunity which persists despite a decline in circulating SARS-CoV-2-antibodies.

Figure 2: After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/science/article/pii/S009286742030475X; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext). [Source: Cevik et al., 2020]

COVID-19 vaccines

There have been multiple COVID-19 vaccines that have been tested in pre-clinical and clinical trial settings., some of which are highlighted in Table 1.
By early 2021, mRNA-1273 (mRNA vaccine; Moderna), BNT162b2 (mRNA vaccine; Pfizer/BioNTech) and Sputnik V (viral vector; Gamaleya) demonstrated over 90% efficacy against acquisition of SARS-CoV-2, while other viral vector vaccines Ad26.COV2.S (Johnson & Johnson) and AZD1222 (ChAdOx1; Oxford/Astra-Zeneca) vaccines didn’t perform as well with efficacies above 50% depending on the region, and as low as 20% for AZD1222 when tested in South Africa.

Table 1: COVID-19 vaccines

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Interested in learning more about COVID-19 vaccines and responses read the following news summaries:

Viral genomic analysis of breakthrough infection in vaccinated individuals highlighted the emergence of SARS-CoV-2 variants (discussed in detail below) which significantly lowered efficacy signal of Ad26.COV2.S (Johnson & Johnson) and AZD1222 (Oxford/Astra-Zeneca), while other vaccine mRNA-1273 (Moderna), BNT162b2 (Pfizer/BioNTech) and Sputnik V (Gamaleya) were tested when the original SARS-CoV-2 variant was still the most prevalent.
All vaccines have been shown to induce robust vaccine induced humoral and cellular immunity and are very efficacious against severe COVID-19 which may require hospitalization or even lead to mortality.
Due to limited global access to COVID-19 vaccines, largely resulting in vaccine inequity in Asia and Africa. Researchers are investigating novel vaccination strategies, such as heterologous prime-boost strategies to facilitate mass COVID-19 vaccinations.
Borobia et al., 2021, demonstrated that BNT162b2 given as a second dose in individuals vaccinated with AZD1222 (ChAdOx1-S) induced a robust immune response, with an acceptable and manageable reactogenicity profile. Additionally immune responses in the heterologous vaccination arm were detected as significantly higher levels that control vaccination arm (Figure 3)

Figure 3: Neutralisation responses (A) Neutralising antibodies measured in both intervention and control groups on days 0 and 14. (B) Correlation between NT50 and RBD (anti-spike protein) antibody titres. NT50=titres that achieved 50% neutralisation. RBD=receptor-binding domain. *p<0·0001. [Source: Borobia et al., 2021]

Correlates of protection

Due to limited knowledge of what protective immune responses are associated with prevention of COVID-19, majority of COVID-19 vaccines were tested without knowledge of a correlate protection of SARS-CoV-2 infection.
What is a correlate of protection? The immune responses that are statistically associated with protection against disease.
Circulating antibodies and neutralizing antibodies are often considered potential correlates of protection against viruses, thus majority of natural SARS-CoV-2 infection and COVID-19 vaccine immunogenicity studies measure the induction of (neutralizing) antibodies (nAbs) as one of the trial endpoints. However, are Abs truly correlate of SARS-CoV-2 protection?
Results from non-human primate models suggest mRNA-1273 vaccine induced Abs detectable in serum and localized at mucosal sites can restrict SARS-CoV-2 replication and confer protection against SARS-CoV-2 infection (Corbett et al., 2021). Further passive immunization of mRNA-1273 vaccine induced Abs mediated protection against SARS-CoV-2 challenge in naïve hamsters (Figure 4).
However, study in humans by Feng et al., demonstrated that though vaccination with AZD1222 induced robust levels of Abs including nAbs, Ab responses were not identified as a correlate of protection. However, vaccine induced humoral immune was associated with a lower risk of severe COVID-19.

Overall these results highlight the need for additional studies, as well as assessing investigating whether cellular immunity is a potential correlate of protection

Figure 4: Passive transfer of mRNA-1273 immune NHP IgG into Syrian hamsters. (A) Sera were pooled from all NHP that received 100 μg of mRNA-1273 in a primary vaccination series. (B) mRNA-1273 immune NHP IgG (2 mg, yellow or 10 mg, orange) or pre-immune NHP IgG (10 mg, gray) was passively transferred to Syrian hamsters (n = 8/group) 24 hours prior to SARS- CoV-2 challenge. Twenty-three hours post-immunization, hamsters were bled to quantify circulating S-specific IgG (C) and SARS-CoV-2 pseudovirus neutralizing antibodies (D). Following challenge, hamsters were monitored for weight loss (E). (C-D) Circles represent individual NHP. Bars and error bars represent GMT and geometric SD, respectively. Asterisks at the axis represent animals that did not receive adequate IgG via passive transfer and were thus excluded from weight loss analyses. (D) The dotted line indicates the neutralization assay limit of detection. (E) Circle and error bars represent mean and SEM, respectively. [Source: Corbett et al., 2021]

SARS-CoV-2 Immune escape: Effect of SARS-CoV-2 variants on pre-existing immune responses

Viruses are known to naturally mutate without impacting the ability of the virus to cause infection nor diseases. However, if mutations occur cumulatively in proteins that are required for viral entry or in epitopes targeted by immune responses this may impact transmissibility or diseases severity of the mutated virus.
SARS-CoV-2 has evolved more rapidly than researchers anticipated, resulting in the evolution of multiple variants (viruses with unique multiple mutations that are distinct from the initial detected SARS-CoV-2 strain). These variants have been divided into variants of concern (VOC) and interests (VOI).
As of 6^th September 2021, there were 4 main VOC (Table 2) which are associated with mutations in the S protein which contribute to either increased transmissibility, increased pathogenicity, or both.
Additionally, mutations in the VOCs contributes to lower Ab neutralisation capacity by nAbs induced naturally or by COVID-19 vaccines, as well hinders the provision of convalescent plasma as a potential treatment for COVID-19.
Interestingly, immune responses induced by the Beta VOC conferred cross-reactive immunity against the Gamma VOC (Moyo-Gwete et al., 2021). The suggests that developing vaccines that included known mutations in the VOC may increase the efficacy of vaccines.

Table 2: SARS-CoV-2 Variants of interest

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Source: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/

Majority of our understanding of immune escape has focused on humoral immunity. However, not much is known whether VOC also escape cellular immunity.
Pre-print by Riou et al., shows that despite loss of recognition of immunodominant CD4 epitope(s) to the spike protein, which represented <20% of the total T cell responses, the overall CD4 and CD8 T cell responses to B.1.351 are preserved.