RESUMO
IntroductionProgress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020. MethodsSystematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results150 papers were included. Most studies (75%) were observational in design, and included papers were generally of moderate quality based on hospitalised patients. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, and up to around 3 months from disease onset, although inconsistencies remain concerning clinical correlates. Development of neutralising antibodies following SARS-CoV-2 infection is typical, although titres may be low. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross reactivity but limited cross neutralisation occurs with other HCoVs. Evidence for protective immunity in vivo is limited to small, short-term animal studies, which show promising initial results in the immediate recovery phase. InterpretationPublished literature on immune responses to SARS-CoV-2 is of variable quality with considerable heterogeneity with regard to methods, study participants, outcomes measured and assays used. Antibody dynamics have been evaluated thoroughly in the acute phase but longer follow up and a comprehensive assessment of the role of demographic characteristics and disease severity is needed. The role of protective neutralising antibodies is emerging, with implications for therapeutics and vaccines. Large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.
RESUMO
IntroductionUnderstanding the cellular immune response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published in recent months. MethodsFor this systematic review, independent keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer for studies published from 01/01/2020-26/06/2020. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results61 articles were included. Almost all studies used observational designs, were hospital-based, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. InterpretationA complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies. In contrast to antibody responses, population-level surveillance of the cellular response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.
RESUMO
A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.
RESUMO
In this study we demonstrate that the adoption of a segmenting and shielding (S&S) strategy could increase scope to partially exit COVID-19 lockdown while limiting the risk of an overwhelming second wave of infection. The S&S strategy has an antecedent in the "cocooning" of infants by immunisation of close family members (Forsyth et al., 2015), and forms a pillar of infection, prevention and control (IPC) strategies (RCN, 2017). We are unaware of it being proposed as a major public health initiative previously. We illustrate the S&S strategy using a mathematical model that segments the vulnerable population and their closest contacts, the "shielders". We explore the effects on the epidemic curve of a gradual ramping up of protection for the vulnerable population and a gradual ramping down of restrictions on the non-vulnerable population over a period of 12 weeks after lockdown. The most important determinants of outcome are: i) post-lockdown transmission rates within the general population segment and between the general and vulnerable segments; ii) the fraction of the population in the vulnerable and shielder segments; iii) adherence with need to be protected; and iv) the extent to which population immunity builds up in all segments. We explored the effects of extending the duration of lockdown and faster or slower transition to post-lockdown conditions and, most importantly, the trade-off between increased protection of the vulnerable segment and fewer restrictions on the general population. We illustrate how the potential for the relaxation of restrictions interacts with specific policy objectives. We show that the range of options for relaxation in the general population can be increased by maintaining restrictions on the shielder segment and by intensive routine screening of shielders. We find that the outcome of any future policy is strongly influenced by the contact matrix between segments and the relationships between physical distancing measures and transmission rates. These relationships are difficult to quantify so close monitoring of the epidemic would be essential during and after the exit from lockdown. More generally, S&S has potential applications for any infectious disease for which there are defined proportions of the population who cannot be treated or who are at risk of severe outcomes.
