Monoclonal antibody levels and protection from COVID-19

Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies in preventing symptomatic SARS-CoV-2 infection. We use data on changes in the in vivo concentration of monoclonal antibodies, and the associated protection from COVID-19, over time to model the dose-response relationship of monoclonal antibodies for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a monoclonal antibody concentration of 54-fold of the in vitro IC50 (95% CI: 16 - 183). This relationship provides a quantitative tool allowing prediction of the prophylactic efficacy and duration of protection for new monoclonal antibodies administered at different doses and against different SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either monoclonal antibody treatment or vaccination. We find no evidence for a difference between the 50% protective titer for monoclonal antibodies and vaccination.

Predicting the efficacy of variant-modified COVID-19 vaccine boosters

As a result of the emergence and circulation of antigenically distinct SARS-CoV-2 variants, a number of variant-modified COVID-19 vaccines have been developed. Here we perform a meta-analysis of the available data on neutralisation titres from clinical studies comparing booster vaccination with either the current ancestral-based vaccines or variant-modified vaccines. We then use this to predict the relative efficacies of these booster vaccines under different scenarios.

Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection

Several studies show neutralizing antibody levels are an important correlate of immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, a number of these studies appear to yield quite different estimates of the level of neutralizing antibodies required for protection. Here we show that after normalization of antibody titers current studies converge on a consistent relationship between antibody levels and protection from COVID-19.

Neutralising antibodies predict protection from severe COVID-19

BackgroundVaccine protection from COVID-19 has been shown to decline with time-since-vaccination and against SARS-CoV-2 variants. Protection against severe COVID-19 is higher than against symptomatic infection, and also appears relatively preserved over time and against variants. Although protection from symptomatic SARS-CoV-2 infection is strongly correlated with neutralising antibody titres, this relationship has been less well described for severe COVID-19. Here we analyse whether neutralising antibody titre remains predictive of protection against severe COVID-19 in the face of waning neutralising antibody levels and emerging variants. MethodsWe extracted data from 15 studies reporting on protection against a range of SARS-CoV-2 clinical endpoints ( any infection, symptomatic infection and severe COVID-19). We then estimated the concurrent neutralising antibody titres using existing parameters on vaccine potency, neutralising antibody decay, and loss of recognition of variants and investigated the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. FindingsPredicted neutralising antibody titres are strongly correlated with vaccine effectiveness against symptomatic and severe COVID-19 (Spearman{rho} = 0.94 and 0.63 respectively, p<.001 for both). The relationship between neutralisation titre and protection is consistent with previous estimates, with 76% (127 of 167) of reported values of protection against severe COVID-19 across a range of vaccines and variants lie within the 95% confidence intervals of the previously published model. InterpretationNeutralising antibody titres are predictive of vaccine effectiveness against severe COVID-19 including in the presence of waning immunity and viral variants. FundingNational Health and Medical Research Council (Australia), Medical Research Future Fund (Australia). O_TEXTBOXEvidence before this study COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection has been shown to be strongly predicted by neutralising antibody titres. However, there has not been sufficient data on vaccine efficacy against severe disease to determine whether the correlation between neutralising antibody titres and protection is maintained for severe COVID-19. Indeed, the apparent faster waning of vaccine efficacy against symptomatic (compared to severe) COVID-19 has led some to hypothesise about a decoupling of protection from symptomatic and severe disease. It is therefore important to identify whether neutralising antibody titre remains a correlate of protection against severe COVID-19 in real-world scenarios of waning immunity and SARS-CoV-2 variants. We searched PubMed between inception and March 2, 2022 for studies (Key search terms: (SARS-CoV-2 OR COVID-19) AND (followup OR waning OR duration OR durable) AND (protection OR efficacy OR effectiveness)) and also monitored other public sources of information such as Twitter. We identified 15 studies that reported data on vaccine effectiveness against (i) a defined clinical endpoint (ii) for an identifiable variant, (ii) for a single vaccine (or vaccine type), (iii) over an identified time since vaccination, and (iv) for which data was either provided in or readily extractable from the original publication. Added value of this study Previous work has identified that neutralising antibodies correlate strongly with protection from symptomatic COVID-19 disease for both ancestral virus and for variants of concern. Here we examine published data on vaccine effectiveness to determine if this correlation remains valid for predicting protection against severe COVID-19. Our work shows that vaccine effectiveness against severe COVID-19 is strongly correlated with neutralising antibody titres for different vaccines, variants, and over the first six months after vaccination. The relationship between vaccine effectiveness and protection against severe COVID-19 is consistent with a previously published analysis and indicates that the 50% protective titre for protection against severe COVID-19 is lower than that associated with protection from symptomatic infection. Implications of all of the available evidence In the face of increased exposure and immunity to numerous SARS-CoV-2 variants it is becoming increasingly important to be able to predict not only protection against symptomatic infection, but also protection against severe COVID-19. Here we show that neutralising antibody titres remain predictive of vaccine effectiveness against severe COVID-19 in the face of waning immunity and SARS-CoV-2 variants. This is consistent with a low level of neutralising antibodies being associated with protection from severe COVID-19. This work will be of use in providing early estimates of protection against severe COVID-19 for new SARS-CoV-2 antigenic variants, informing optimal booster timing, and will support future vaccine development by allowing prediction of vaccine protection conferred against severe outcomes. C_TEXTBOX

Determinants of passive antibody effectiveness in SARS-CoV-2 infection

BackgroundA large number of studies have been carried out involving passive antibody administration for the treatment and prophylaxis of COVID-19 and have shown variable efficacy. However, the determinants of treatment effectiveness have not been identified. Here we aimed to aggregate all available data on randomised controlled trials of passive antibody treatment for COVID-19 to understand how the dose and timing affect treatment outcome. MethodsWe analysed published studies of passive antibody treatment from inception to 7 January 2022 that were identified after searching various databases such as MEDLINE, Pubmed, ClinicalTrials.gov. We extracted data on treatment, dose, disease stage at treatment, and effectiveness for different clinical outcomes from these studies. To compare administered antibody levels between different treatments, we used data on in vitro neutralisation of pseudovirus to normalise the administered dose of antibody. We used a mixed-effects regression model to understand the relationship between disease stage at treatment and effectiveness. We used a logistic model to analyse the relationship between administered antibody dose (normalised to the mean convalescent titre) and outcome, and to predict efficacy of antibodies against different Omicron subvariants. FindingsWe found that clinical stage at treatment was highly predictive of the effectiveness of both monoclonal antibodies and convalescent plasma therapy in preventing progression to subsequent stages (p<0.0001 and p=0.0089, respectively, chi-squared test). We also analysed the dose-response curve for passive antibody treatment of ambulant COVID-19 patients to prevent hospitalisation. Using this quantitative dose-response relationship, we predict that a number of existing monoclonal antibody treatment regimens should maintain clinical effectiveness in infection with currently circulating Omicron variants. InterpretationEarly administration of passive antibody therapy is crucial to achieving high efficacy in preventing clinical progression. A dose-response curve was derived for passive antibody therapy administered to ambulant symptomatic subjects to prevent hospitalisation. For many of the monoclonal antibody regimens analysed, the administered doses are estimated to be between 7 and >1000 fold higher than necessary to achieve 90% of the maximal efficacy against the ancestral (Wuhan-like) virus. This suggests that a number of current treatments should maintain high efficacy against Omicron subvariants despite reduction in in vitro neutralisation potency. This work provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. FundingThis work is supported by an Australian government Medical Research Future Fund awards GNT2002073 and MRF2005544 (to MPD, SJK), MRF2005760 (to MPD), an NHMRC program grant GNT1149990 (SJK and MPD), and the Victorian Government (SJK). SJK is supported by a NHMRC fellowship. DC, MPD, ZKM and EMW are supported by NHMRC Investigator grants and ZKM and EMW by an NHMRC Synergy grant (1189490). DSK is supported by a University of New South Wales fellowship. KLC is supported by PhD scholarships from Monash University, the Haematology Society of Australia and New Zealand and the Leukaemia Foundation. TT, HW and CB are members of the National COVID-19 Clinical Evidence Taskforce which is funded by the Australian Government Department of Health. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe identified randomised controlled trials (RCTs) evaluating the effectiveness of SARS-CoV-2-specific neutralising monoclonal antibodies, hyperimmune immunoglobulin and convalescent plasma in the treatment of participants with a confirmed diagnosis of COVID-19 and in uninfected participants with or without potential exposure to SARS-CoV-2. The RCTs were identified from published searches conducted by the Cochrane Haematology living systematic review teams. A total of 37 randomised controlled trials (RCT) of passive antibody administration for COVID-19 were identified. This included 12 trials on monoclonal antibodies, 21 trials of convalescent plasma treatment, and 4 trials of hyperimmune globulin. These trials involved treatment of individuals either prophylactically or at different stages of infection including post-exposure prophylaxis, symptomatic infection, and hospitalisation. The level of antibody administered ranged from a 250 ml volume of convalescent plasma through to 8 grams of monoclonal antibodies. Data for analysis was extracted from the original publications including dose and antibody levels of antibody administered, disease stage and timing of administration, primary outcome of study and whether they reported on our prespecified outcomes of interest, which include protection against symptomatic infection, hospitalisation, need for invasive mechanical ventilation (IMV) and death (all-cause mortality at 30 days). Added value of this studyOur study included data across all 37 RCTs of passive antibody interventions for COVID-19 and aggregated the studies by the stage of infection at initiation of treatment. We found that prophylactic administration or treatment in earlier stages of infection had significantly higher effectiveness than later treatment. We also estimated the dose-response relationship between administered antibody dose and protection from progression from symptomatic ambulant COVID-19 to hospitalisation. We used this relationship to predict the efficacy of different monoclonal antibody treatment regimes against the Omicron subvariants BA.1, BA.2, and BA.4/5. We also used this dose-response relationship to estimate the maximal efficacy of monoclonal antibody therapy in the context of pre-existing endogenous neutralising antibodies. Implications of all the available evidenceThis work identifies that both prophylactic therapy and treatment in the early stages of symptomatic infection can achieve significant protection from infection or hospitalisation respectively. The dose-response relationship provides a quantitative means to predict the change in efficacy of different monoclonal antibodies against new variants and in semi-immune populations based on in vitro neutralisation data. We predict a number of existing monoclonal antibodies will be effective for preventing severe outcomes when administered early in BA.4/5 infections. It is likely that these therapies will provide little protection in individuals with high levels of endogenous neutralising antibodies, such as healthy individuals who have recently received a third dose of an mRNA vaccine.

Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine

Despite a clear role in protective immunity, the durability and quality of antibody and memory B cell responses induced by mRNA vaccination, particularly by a 3rd dose of vaccine, remains unclear. Here, we examined antibody and memory B cell responses in a cohort of individuals sampled longitudinally for [~]9-10 months after the primary 2-dose mRNA vaccine series, as well as for [~]3 months after a 3rd mRNA vaccine dose. Notably, antibody decay slowed significantly between 6- and 9-months post-primary vaccination, essentially stabilizing at the time of the 3rd dose. Antibody quality also continued to improve for at least 9 months after primary 2-dose vaccination. Spike- and RBD-specific memory B cells were stable through 9 months post-vaccination with no evidence of decline over time, and [~]40-50% of RBD-specific memory B cells were capable of simultaneously recognizing the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells induced by the first 2 doses of mRNA vaccine were boosted significantly by a 3rd dose and the magnitude of this boosting was similar to memory B cells specific for other variants. Pre-3rd dose memory B cell frequencies correlated with the increase in neutralizing antibody titers after the 3rd dose. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit reactivation of immunological memory and constrain further antibody boosting by mRNA vaccines. These data provide a deeper understanding of how the quantity and quality of antibody and memory B cell responses change over time and number of antigen exposures. These data also provide insight into potential immune dynamics following recall responses to additional vaccine doses or post-vaccination infections. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/481163v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@123d2d9org.highwire.dtl.DTLVardef@e7db82org.highwire.dtl.DTLVardef@1fc73deorg.highwire.dtl.DTLVardef@11b21f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

Dynamics of immune recall following SARS-CoV-2 vaccination or breakthrough infection

Vaccination against SARS-CoV-2 results in protection from acquisition of infection as well as improved clinical outcomes even if infection occurs, likely reflecting a combination of residual vaccine-elicited immunity and the recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and T cell immunity after vaccination of seropositive individuals, and after breakthrough infection in vaccinated individuals. Intensive and early longitudinal sampling reveals the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titres. In breakthrough infections, the delayed kinetics of humoral immune recall provides a mechanism for the lack of early control of viral replication but likely underpins accelerated viral clearance and the protective effects of vaccination against severe COVID-19.

SARS-CoV-2 Omicron: reduction of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and / or previously infected individuals; concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise virus in vitro. There was a 17 to 22-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of individuals infected with the Omicron variant.

Analysis: A meta-analysis of Early Results to predict Vaccine efficacy against Omicron

In the studies to date, the estimated fold-drop in neutralisation titre against Omicron ranges from 2- to over 20-fold depending on the study and serum tested. Collating data from the first four of these studies results in a combined estimate of the drop in neutralisation titre against Omicron of 9.7-fold (95% CI 5.5-17.1). We use our previously established model to predict that six months after primary immunisation with an mRNA vaccine, efficacy for Omicron is estimated to have waned to around 40% against symptomatic and 80% against severe disease. A booster dose with an existing mRNA vaccine (even though it targets the ancestral spike) has the potential to raise efficacy for Omicron to 86.2% (95% CI: 72.6-94) against symptomatic infection and 98.2% (95% CI: 90.2-99.7) against severe infection.

SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection

The emergence of SARS-CoV-2 Omicron, first identified in Botswana and South Africa, may compromise vaccine effectiveness and the ability of antibodies triggered by previous infection to protect against re-infection (1). Here we investigated whether Omicron escapes antibody neutralization in South Africans, either previously SARS-CoV-2 infected or uninfected, who were vaccinated with Pfizer BNT162b2. We also investigated if Omicron requires the ACE2 receptor to infect cells. We isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralization of this virus relative to an ancestral SARS-CoV-2 strain with the D614G mutation, observing that Omicron still required ACE2 to infect. For neutralization, blood samples were taken soon after vaccination, so that vaccine elicited neutralization was close to peak. Neutralization capacity of the D614G virus was much higher in infected and vaccinated versus vaccinated only participants but both groups had 22-fold Omicron escape from vaccine elicited neutralization. Previously infected and vaccinated individuals had residual neutralization predicted to confer 73% protection from symptomatic Omicron infection, while those without previous infection were predicted to retain only about 35%. Both groups were predicted to have substantial protection from severe disease. These data support the notion that high neutralization capacity elicited by a combination of infection and vaccination, and possibly boosting, could maintain reasonable effectiveness against Omicron. A waning neutralization response is likely to decrease vaccine effectiveness below these estimates. However, since protection from severe disease requires lower neutralization levels and involves T cell immunity, such protection may be maintained.

mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naive and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/457229v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@16c64b1org.highwire.dtl.DTLVardef@146ca3aorg.highwire.dtl.DTLVardef@86b7edorg.highwire.dtl.DTLVardef@956879_HPS_FORMAT_FIGEXP M_FIG C_FIG

SARS-CoV-2 variants: levels of neutralisation required for protective immunity

A number of SARS-CoV-2 variants of concern (VOC) have been identified that partially escape serum neutralisation activity elicited by current vaccines. Recent studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. Here we integrate published data on in vitro neutralisation and clinical protection to understand and predict vaccine efficacy against existing SARS-CoV-2 variants. We find that neutralising activity against the ancestral SARS-CoV-2 is highly predictive of neutralisation of the VOC, with all vaccines showing a similar drop in neutralisation to the variants. Neutralisation levels remain strongly correlated with protection from infection with SARS-CoV-2 VOC (r=0.81, p=0.0005). We apply an existing model relating in vitro neutralisation to protection (parameterised on data from ancestral virus infection) and find this remains predictive of vaccine efficacy against VOC once drops in neutralisation to the VOC are taken into account. Modelling of predicted vaccine efficacy against variants over time suggests that protection against symptomatic infection may drop below 50% within the first year after vaccination for some current vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) has been shown to significantly increase neutralising antibodies. Our modelling suggests that booster vaccination should enable high levels of immunity that prevent severe infection outcomes with the current SARS-CoV-2 VOC, at least in the medium term.

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial.

A recent study analysed the relationship between neutralising antibody response and protection from SARS-CoV-2 infection across eight vaccine platforms1. The efficacy results from a phase 2b/3 trial of a ninth vaccine candidate, CVnCoV (CUREVAC), was announced on 16 June 20212. The low efficacy of this new mRNA vaccine, which showed only 47% protection from symptomatic SARS-CoV-2 infection, was surprising given the high efficacy of two previous mRNA-based vaccines3,4. A number of factors have been suggested to play a role in the low efficacy in the CVnCoV study, particularly around the dose and immunogenicity of the vaccine (which uses an unmodified mRNA construct5,6) and the potential role of infection with SARS-CoV-2 variants (which were the dominant strains observed in the CVnCoV trial)2.

What level of neutralising antibody protects from COVID-19? .

Both previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

Evolution of immunity to SARS-CoV-2

The durability of infection-induced SARS-CoV-2 immunity has major implications for public health mitigation and vaccine development. Animal studies1,2 and the scarcity of confirmed re-infection3 suggests immune protection is likely, although the durability of this protection is debated. Lasting immunity following acute viral infection requires maintenance of both serum antibody and antigen-specific memory B and T lymphocytes and is notoriously pathogen specific, ranging from life-long for smallpox or measles4, to highly transient for common cold coronaviruses (CCC)5. Neutralising antibody responses are a likely correlate of protective immunity and exclusively recognise the viral spike (S) protein, predominantly targeting the receptor binding domain (RBD) within the S1 sub-domain6. Multiple reports describe waning of S-specific antibodies in the first 2-3 months following infection7-12. However, extrapolation of early linear trends in decay might be overly pessimistic, with several groups reporting that serum neutralisation is stable over time in a proportion of convalescent subjects8,12-17. While SARS-CoV-2 specific B and T cell responses are readily induced by infection6,13,18-24, the longitudinal dynamics of these key memory populations remains poorly resolved. Here we comprehensively profiled antibody, B and T cell dynamics over time in a cohort recovered from mild-moderate COVID-19. We find that binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection, as expected, with a similar decline in S-specific CD4+ and circulating T follicular helper (cTFH) frequencies. In contrast, S-specific IgG+ memory B cells (MBC) consistently accumulate over time, eventually comprising a significant fraction of circulating MBC. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent subjects to 74 days, with probable additive protection from B and T cells. Overall, our study suggests SARS-CoV-2 immunity after infection is likely to be transiently protective at a population level. SARS-CoV-2 vaccines may require greater immunogenicity and durability than natural infection to drive long-term protection.