Immune responses and immunity to SARS-CoV-2
(last update 18 May 2021)
Immune responses and correlates of protective immunity against SARS-CoV-2
Correlates of protective immunity to a pathogen are measurable signs that reliably identify individuals as protected against specific outcomes, such as infection, transmission risk, or disease outcome. Following infection with SARS-CoV-2 or vaccination, it is the adaptive immune response that ideally delivers long-term protection. The adaptive immune response primarily comprises memory B cells that produce different classes of antibody to neutralise the virus or virus-infected cells, and memory T cells that support antibody production and also have a direct role in killing virus-infected cells. While there is evidence of both memory B cell and T cell immune responses in individuals infected with SARS-CoV-2 as well as in vaccinated persons, clear correlates for protective immunity have yet to be defined [1-4]. In the absence of definitive correlates of protective immunity, the presence of neutralising antibodies against SARS-CoV-2 provides the best current indication for protection against reinfection for previously infected individuals, or breakthrough infection in vaccinated individuals. The S1 domain of the SARS-CoV-2 spike protein includes the receptor-binding domain (RBD), and antibodies targeting this critically impair virus cell entry . A number of studies have shown that neutralisation ability of polyclonal antibodies in serum correlate positively with anti-spike IgG or anti-RBD IgG .
Immune responses following natural infection
A systematic review of 150 studies describing virus-specific serum antibody responses in individuals infected with SARS-CoV-2 showed IgM is consistently detected before IgG, peaking between weeks two and five and declining over a further three- to five-week period post-symptom onset. IgG peaks between weeks three and seven post-symptom onset, persisting for at least eight weeks. Neutralising antibodies – with the capacity to restrict virus growth in vitro – are detectable within seven to 15 days of disease onset, and levels increase until days 14-22, before plateauing and then decreasing. Lower antibody titres have been observed in those with asymptomatic or clinically mild disease. However, the review in question primarily featured observational studies of hospitalised cases, with follow-up periods lasting up to three months post-symptom onset. Critically, there is considerable heterogeneity in the types of assays used, as well as the SARS-CoV-2 proteins they target . As with B cell immunity, T cell immunity develops over a period of at least 10-20 days post-symptom onset. A systematic review of 61 studies indicated that increasing disease severity is associated with more robust, virus-specific T cell responses . Studies of T cell responses are also affected by heterogeneity in the types of assays used, and there is limited data on infected individuals who are asymptomatic or pauci-symptomatic [3,4,6].
Immune responses following vaccination
The assessment of immune responses induced by vaccination has largely focussed on the development of antibodies targeting the S1 domain of the SARS-CoV-2 spike protein. A key benefit of some vaccine regimens is that anti-S IgG titres are higher than for natural infection, with serum from vaccinated individuals showing greater neutralisation capacity against homologous SARS-CoV-2 viruses in vitro . While vaccination has been shown to result in robust T cell responses – memory and effector function have been demonstrated against multiple viral epitopes – the significance of T cell responses for protection and susceptibility at population level, independent of memory B cell responses, remains unclear [3,6,8,9].
Duration of protective immunity
Although virus-specific B cell and T cell responses are evident shortly into the recovery from infection or vaccination, they are prone to wane over time, with decreasing numbers of circulating virus-specific memory T cells, memory B cells, and serum antibodies. Consequently, protection against outcomes such as infection, transmission risk, or severe disease may also wane over time. Assessing the impact of waning immunity requires careful evaluation of both the quantitative reduction in immune readouts and the qualitative or functional change over time. It is also important to consider the interdependency of readouts assessing T cells, B cells, or antibodies. In a long-term follow-up study of 25 individuals infected with SARS-CoV-2, virus-specific memory B cells were identified in the early stages of convalescence. While serum antibodies peaked 20 days post-infection before waning, virus-specific memory B cells persisted for over 242 days post-symptom onset . This study highlights that a decline in serum antibodies in convalescence may not reflect waning immunity, but rather a contraction of the immune response, with the development and persistence of virus-specific, long-lived B cells in bone marrow [10-12]. Similarly, the development of memory T cells directed at non-surface SARS-CoV-2 proteins following infection or vaccination may offer a route to durable immunity where virus evolution leads to spike protein mutations that escape pre-existing neutralising antibodies . This will occur either by offering more efficient support to activated naïve B cells responding to the altered spike protein (memory CD4 T cells), or through direct lysis of SARS-CoV-2 infected cells (CD8 T cells) [12,13].
The vast majority of SARS-CoV-2-infected individuals seroconvert following SARS-CoV-2 infection. Reviews of the published literature indicate that >90% patients develop IgG seropositivity and neutralising antibodies following primary infection, ranging between 91 and 99% in large studies [2,12]. A scoping review performed by the Irish Health Information and Quality Authority (HIQA) to evaluate the long-term duration of immune responses following SARS-CoV-2 infection identified five studies that investigated immune responses at ≥6 months post-infection, including two studies at ≥8 months post-infection. In general, studies reported a waning of antibody responses in the late convalescent period (3-6 months post-infection). However, T-cell and memory B-cell responses were still present, and in many cases increased, up to eight months post-infection in all study participants . Taken together, results from cohort studies confirm the protective effect of previous SARS-CoV-2 infection ranges from 81% to 100% during a follow-up period of five to seven months [15-20].
A prospective cohort study from Singapore has evaluated the dynamics of SARS-CoV-2 neutralising antibody responses over time. Serum samples were collected at approximately 30-day intervals up to 180 days post-symptom onset from 164 patients with PCR-confirmed SARS-CoV-2 infection experiencing mild, moderate, or severe disease. The authors described five distinctive patterns of neutralising antibody dynamics:
- negative – individuals who did not develop strong neutralising antibody responses: 19/164 patients (12%);
- rapid waning – individuals who had varying levels of neutralising antibodies from around 20 days after symptom onset, but seroconverted in less than 180 days: 44/164 patients (27%);
- slow waning – individuals who remained neutralising antibody-positive at 180 days post-symptom onset: 52/164 patients (29%);
- persistent – individuals with varying peak neutralising antibody levels, but minimal neutralising antibody decay: 52/164 patients (32%); and
- delayed response – individuals with neutralising antibodies present at lower levels shortly after infection that showed an unexpected increase during late convalescence (at 90 or 180 days after symptom onset: 3/164 patients (2%).
Greater disease severity was associated with persistent neutralising antibody levels, and patients with milder disease appeared to have more rapid neutralising antibody waning. While this study showed that neutralising antibody dynamics can vary greatly among individual patients with COVID-19, development and persistence of virus-specific, long-lived memory B cells was not studied. However, the authors did analyse 23 randomly selected patients from the five categories described, confirming the presence of virus-specific memory T-cells at 180 days post-symptom onset in patients from each of the five categories .
Follow-up periods for previously infected and vaccinated individuals are not yet sufficiently long enough to be able to draw conclusions on the duration of protection against infection beyond 6 months for those vaccinated or beyond 12 months post-natural infection. The emergence of SARS-CoV-2 variants of concern (VOC)  demonstrating increased transmissibility, severity, and immune escape potential also underscore the need for additional population level studies evaluating both the durability and cross-reactivity of B cell and T cell responses to variant viruses [8,9].