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1.
Cell Rep Med ; 3(9): 100739, 2022 09 20.
Article in English | MEDLINE | ID: covidwho-2004612

ABSTRACT

Age is the strongest determinant of COVID-19 mortality, and over 2 billion people have received primary series vaccination with BNT162b2 (mRNA) or ChAdOx1 (adenoviral vector). However, the profile of sustained vaccine immunogenicity in older people is unknown. Here, we determine spike-specific humoral and cellular immunity to 8 months following BNT162b2 or ChAdOx1 in 245 people aged 80-98 years. Vaccines are strongly immunogenic, with antibodies retained in every donor, while titers fall to 23%-26% from peak. Peak immunity develops rapidly with standard interval BNT162b2, although antibody titers are enhanced 3.7-fold with extended interval. Neutralization of ancestral variants is superior following BNT162b2, while neutralization of Omicron is broadly negative. Conversely, cellular responses are stronger following ChAdOx1 and are retained to 33%-60% of peak with all vaccines. BNT162b2 and ChAdOx1 elicit strong, but differential, sustained immunogenicity in older people. These data provide a baseline to assess optimal booster regimen in this vulnerable age group.


Subject(s)
COVID-19 Vaccines , COVID-19 , Aged , BNT162 Vaccine , COVID-19/prevention & control , Humans , Immunogenicity, Vaccine , RNA, Messenger
2.
Lancet Healthy Longev ; 3(7): e461-e469, 2022 07.
Article in English | MEDLINE | ID: covidwho-1915222

ABSTRACT

Background: Older age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for individuals with these factors, but there is concern that immune responses might be impaired due to age-related immune dysregulation and comorbidity. We aimed to study humoral and cellular responses to COVID-19 vaccines in residents of long-term care facilities (LTCFs). Methods: In this observational cohort study, we assessed antibody and cellular immune responses following COVID-19 vaccination in members of staff and residents at 74 LTCFs across the UK. Staff and residents were eligible for inclusion if it was possible to link them to a pseudo-identifier in the COVID-19 datastore, if they had received two vaccine doses, and if they had given a blood sample 6 days after vaccination at the earliest. There were no comorbidity exclusion criteria. Participants were stratified by age (<65 years or ≥65 years) and infection status (previous SARS-CoV-2 infection [infection-primed group] or SARS-CoV-2 naive [infection-naive group]). Anticoagulated edetic acid (EDTA) blood samples were assessed and humoral and cellular responses were quantified. Findings: Between Dec 11, 2020, and June 27, 2021, blood samples were taken from 220 people younger than 65 years (median age 51 years [IQR 39-61]; 103 [47%] had previously had a SARS-CoV-2 infection) and 268 people aged 65 years or older of LTCFs (median age 87 years [80-92]; 144 [43%] had a previous SARS-CoV-2 infection). Samples were taken a median of 82 days (IQR 72-100) after the second vaccination. Antibody responses following dual vaccination were strong and equivalent between participants younger then 65 years and those aged 65 years and older in the infection-primed group (median 125 285 Au/mL [1128 BAU/mL] for <65 year olds vs 157 979 Au/mL [1423 BAU/mL] for ≥65 year olds; p=0·47). The antibody response was reduced by 2·4-times (467 BAU/mL; p≤0·0001) in infection-naive people younger than 65 years and 8·1-times (174 BAU/mL; p≤0·0001) in infection-naive residents compared with their infection-primed counterparts. Antibody response was 2·6-times lower in infection-naive residents than in infection-naive people younger than 65 years (p=0·0006). Impaired neutralisation of delta (1.617.2) variant spike binding was also apparent in infection-naive people younger than 65 years and in those aged 65 years and older. Spike-specific T-cell responses were also significantly enhanced in the infection-primed group. Infection-naive people aged 65 years and older (203 SFU per million [IQR 89-374]) had a 52% lower T-cell response compared with infection-naive people younger than 65 years (85 SFU per million [30-206]; p≤0·0001). Post-vaccine spike-specific CD4 T-cell responses displayed single or dual production of IFN-γ and IL-2 were similar across infection status groups, whereas the infection-primed group had an extended functional profile with TNFα and CXCL10 production. Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naive residents of LTCFs, and they suggest the need for optimisation of immune protection through the use of booster vaccination. Funding: UK Government Department of Health and Social Care.


Subject(s)
COVID-19 , Vaccines , Aged, 80 and over , Antibodies, Viral , COVID-19 Vaccines , Humans , Immunity, Cellular , Long-Term Care , Middle Aged , SARS-CoV-2 , Vaccination
3.
Front Immunol ; 13: 882515, 2022.
Article in English | MEDLINE | ID: covidwho-1903016

ABSTRACT

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.


Subject(s)
COVID-19 Vaccines , COVID-19 , 2019-nCoV Vaccine mRNA-1273 , Adolescent , Adult , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Child , Humans , RNA, Messenger , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , mRNA Vaccines
5.
J Infect Dis ; 2022 Apr 16.
Article in English | MEDLINE | ID: covidwho-1883018

ABSTRACT

General population studies have shown strong humoral response following SARS-CoV-2 vaccination with subsequent waning of anti-spike antibody levels. Vaccine-induced immune responses are often attenuated in frail and older populations, but published data are scarce. We measured SARS-CoV-2 anti-spike antibody levels in Long-Term Care Facility residents and staff following second vaccination dose with Oxford-AstraZeneca or Pfizer-BioNTech. Vaccination elicited robust antibody responses in older residents, suggesting comparable levels of vaccine-induced immunity to that in the general population. Antibody levels are higher after Pfizer-BioNTech vaccination but fall more rapidly compared to Oxford-AstraZeneca recipients and are enhanced by prior infection in both groups.

6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334389

ABSTRACT

Third dose COVID-19 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable elderly people who exhibit suboptimal responses after primary series vaccination. We studied spike-specific immune responses in 341 staff and residents in long-term care facilities (LTCF) who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third dose vaccination strongly increased antibody responses with preferential enhancement in older people and was required to elicit neutralisation of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titres fell 21-78% within 100 days post vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a 3rd vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.

7.
Immun Ageing ; 18(1): 34, 2021 Aug 20.
Article in English | MEDLINE | ID: covidwho-1759763

ABSTRACT

BACKGROUND: Several SARS-CoV-2 vaccines have shown clinical efficacy against Covid-19 infection but there remains uncertainty about the immune responses elicited by different regimens. This is a particularly important question for older people who are at increased clinical risk following infection and in whom immune senescence may limit vaccine responses. The BNT162b2 mRNA and ChAdOx1 adenovirus vaccines were the first two vaccines deployed in the UK programme using an 8-12 week 'extended interval'. OBJECTIVES: We undertook analysis of the spike-specific antibody and cellular immune response in 131 participants aged 80+ years after the second dose of 'extended interval' dual vaccination with either BNT162b2 mRNA (n = 54) or ChAdOx1 (n = 77) adenovirus vaccine. Blood samples were taken 2-3 weeks after second vaccine and were paired with samples taken at 5-weeks after first vaccine which have been reported previously. Antibody responses were measured using the Elecsys® electrochemiluminescence immunoassay assay and cellular responses were assessed by IFN-γ ELISpot. RESULTS: Antibody responses against spike protein became detectable in all donors following dual vaccination with either vaccine. 4 donors had evidence of previous natural infection which is known to boost vaccine responses. Within the 53 infection-naïve donors the median antibody titre was 4030 U/ml (IQR 1892-8530) following BNT162b2 dual vaccination and 1405 (IQR 469.5-2543) in the 74 patients after the ChAdOx1 vaccine (p = < 0.0001). Spike-specific T cell responses were observed in 30% and 49% of mRNA and ChAdOx1 recipients respectively and median responses were 1.4-times higher in ChAdOx1 vaccinees at 14 vs 20 spots/million respectively (p = 0.022). CONCLUSION: Dual vaccination with BNT162b2 or ChAdOx1 induces strong humoral immunity in older people following an extended interval protocol. Antibody responses are 2.9-times higher following the mRNA regimen whilst cellular responses are 1.4-times higher with the adenovirus-based vaccine. Differential patterns of immunogenicity are therefore elicited from the two vaccine platforms. It will be of interest to assess the relative stability of immune responses after these homologous vaccine regimens in order to assess the potential need for vaccine boosting. Furthermore, these findings indicate that heterologous vaccine platforms may offer the opportunity to further optimize vaccine responses.

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-323027

ABSTRACT

Background: Residents of long-term care facilities (LTCF) have experienced high mortality rates from SARS-CoV-2 infection and as such have been prioritized for Covid-19 vaccination. Several countries have implemented an extended interval of up to 12 weeks between first and second vaccine doses to increase population coverage after single administration. Methods: Spike-specific immune responses that were induced following single administration of BNT162b2 or ChAdOx1 were studied in 89 staff and 35 residents within LTCFs. Quantitative antibody and cellular responses were determined as well as antibody inhibition of spike protein-ACE2 binding from viral variants. Results: 20% of staff and 34% of residents were found to have serological evidence of prior SARS-CoV-2 infection and all of these donors demonstrated strong antibody responses that were independent of age. Antibody responses were detectable within 99% and 79% of ‘infection-naive’ staff and residents respectively but were 8.2-fold lower within residents. This effect resulted from slower kinetics of antibody generation within residents which reached levels comparable to staff after only 42 days. In contrast spike-specific cellular responses were equivalent between both groups. Antibody inhibition activity against the B.1.351 and P.1 viral variants of concern was low using serum from ‘infection-naive’ older donors. Prior history of natural infection thus has a marked impact on the magnitude and quality of antibody response after a single Covid-19 vaccine in care home residents. Interpretation: Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and might be considered for an early second vaccine where possible. Funding: UK Government Department of Health and Social CareDeclaration of Interests: LS reports grants from the Department of Health and Social Care during the conduct of the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health.Ethics Approval Statement: Ethical approval for this study was obtained from the South Central - Hampshire B Research Ethics Committee, REC Ref: 20/SC/023.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318752

ABSTRACT

Background: B cell chronic lymphocytic leukaemia (CLL) is associated with immune suppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination.Methods: We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 13 patients underwent a standard interval (3-week) vaccine regimen whilst 286 underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. 267 samples were taken at 5 weeks after the first vaccine for patients on the extended interval regimen and 13 and 42 samples were taken at 2-4 weeks after the second vaccine in patients on the standard or extended vaccine regimens respectively.Findings: Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine, compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine.Interpretation: Antibody responses after both the first and second Covid-19 vaccine are lower in patients with CLL compared to age-matched donors. This is particularly marked in patients who are taking BTK inhibitors or have serum IgA deficiency. Further approaches such as repeat vaccination or administration of prophylactic antibody may be worthy of investigation for some patients. Funding Information: This work was partially supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by DHSC/UKRI and the National Core Studies Immunity programme.Declaration of Interests: None to declare. Ethics Approval Statement: The work was performed under the CIA UPH IRAS approval (REC 20W\0240) and conducted according to the Declaration of Helsinki and good clinical practice. Ethical approval was obtained from North West Preston Research Ethics Committee with favourable outcome. Informed consent was obtained in person or by remote consultation.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318750

ABSTRACT

Background: Several SARS-CoV-2 vaccines have shown clinical efficacy against Covid-19 infection but there remains uncertainty about the immune responses elicited by different regimens. This is a particularly important question for older people who are at increased clinical risk following infection and in whom immune senescence may limit vaccine responses. The BNT162b2 mRNA and ChAdOx1 adenovirus vaccines were the first two vaccines deployed in the UK programme using an 8-12 week ‘extended interval’. Objectives: We undertook analysis of the spike-specific antibody and cellular immune response in 131 participants aged 80+ years after the second dose of ‘extended interval’ dual vaccination with either BNT162b2 mRNA (n=54) or ChAdOx1 (n=77) adenovirus vaccine. Blood samples were taken 2-3 weeks after second vaccine and were paired with samples taken at 5-weeks after first vaccine which have been reported previously. Antibody responses were measured using the Elecsys® electrochemiluminescence immunoassay assay and cellular responses were assessed by IFN-g ELISpot. Results: Antibody responses against spike protein became detectable in all donors following dual vaccination with either vaccine. 4 donors had evidence of previous natural infection which is known to boost vaccine responses. Within the 53 infection-naïve donors the median antibody titre was 4030 U/ml (IQR 1892-8530) following BNT162b2 dual vaccination and 1405 (IQR 469.5- 2543) in the 74 patients after the ChAdOx1 vaccine (p=<0.0001). Spike-specific T cell responses were observed in 30% and 49% of mRNA and ChAdOx1 recipients respectively and median responses were 1.4-times higher in ChAdOx1 vaccinees at 14 vs 20 spots/million respectively (p=0.022). Conclusion: Dual vaccination with BNT162b2 or ChAdOx1 induces strong humoral immunity in older people following an extended interval protocol. Antibody responses are 2.9-times higher following the mRNA regimen whilst cellular responses are 1.7-times higher with the adenovirus-based vaccine. Differential patterns of immunogenicity are therefore elicited from the two vaccine platforms. It will be of interest to assess the relative stability of immune responses after these homologous vaccine regimens in order to assess the potential need for vaccine boosting. Furthermore, these findings indicate that heterologous vaccine platforms may offer the opportunity to further optimize vaccine responses.

11.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327186

ABSTRACT

Background General population studies have shown strong humoral response following SARS-CoV-2 vaccination with subsequent waning of anti-spike antibody levels. Vaccine-induced immune responses are often attenuated in frail and older populations such as Long-Term Care Facility (LTCF) residents but published data are scarce. Methods VIVALDI is a prospective cohort study in England which links serial blood sampling in LTCF staff and residents to routine healthcare records. We measured quantitative titres of SARS-CoV-2 anti-spike antibodies in residents and staff following second vaccination dose with ChAdOx1 nCov-19 (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech). We investigated differences in peak antibody levels and rates of decline using linear mixed effects models. Results We report on 1317 samples from 402 residents (median age 86 years, IQR 78-91) and 632 staff (50 years, 37-58), ≤280 days from second vaccination dose. Peak antibody titres were 7.9-fold higher after Pfizer-BioNTech vaccine compared to Oxford-AstraZeneca (95%CI 3.6-17.0;P <0.01) but rate of decline was increased, and titres were similar at 6 months. Prior infection was associated with higher peak antibody levels in both Pfizer-BioNTech (2.8-fold, 1.9-4.1;P <0.01) and Oxford-AstraZeneca (4.8-fold, 3.2-7.1;P <0.01) recipients and slower rates of antibody decline. Increasing age was associated with a modest reduction in peak antibody levels for Oxford-AstraZeneca recipients. Conclusions Double-dose vaccination elicits robust and stable antibody responses in older LTCF residents, suggesting comparable levels of vaccine-induced immunity to that in the general population. Antibody levels are higher after Pfizer-BioNTech vaccination but fall more rapidly compared to Oxford-AstraZeneca recipients and are enhanced by prior infection in both groups.

12.
NPJ Vaccines ; 7(1): 14, 2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1655583

ABSTRACT

The BNT162b2 vaccine is highly effective against COVID-19 infection and was delivered with a 3-week time interval in registration studies1. However, many countries extended this interval to accelerate population coverage with a single vaccine. It is not known how immune responses are influenced by delaying the second dose. We provide the assessment of immune responses in the first 14 weeks after standard or extended-interval BNT162b2 vaccination and show that delaying the second dose strongly boosts the peak antibody response by 3.5-fold in older people. This enhanced antibody response may offer a longer period of clinical protection and delay the need for booster vaccination. In contrast, peak cellular-specific responses were the strongest in those vaccinated on a standard 3-week vaccine interval. As such, the timing of the second dose has a marked influence on the kinetics and magnitude of the adaptive immune response after mRNA vaccination in older people.

13.
Nat Immunol ; 23(1): 40-49, 2022 01.
Article in English | MEDLINE | ID: covidwho-1585824

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens.


Subject(s)
Antibodies, Viral/immunology , Coronavirus 229E, Human/immunology , Coronavirus OC43, Human/immunology , Cross Protection/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adaptive Immunity/immunology , Adult , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Child , Child, Preschool , Cross Reactions/immunology , Humans
14.
SSRN; 2021.
Preprint in English | SSRN | ID: ppcovidwho-297180

ABSTRACT

Background: Age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for this group but there is concern that immune responses may be impaired due to immune senescence and co-morbidity. Methods: We studied antibody and cellular immune responses following COVID-19 vaccination in 202 staff and 286 residents of long-term care facilities (LTCF). Due to the high prevalence of previous infection within this environment 50% and 51% of these two groups respectively had serological evidence of prior natural SARS-CoV-2 infection. Results: In both staff and residents with previous infection the antibody responses following dual vaccination were strong and equivalent across the age course. In contrast, within infection-naïve donors these responses were reduced by 2.4-fold and 8.1-fold respectively such that values within the resident population were 2.6-fold lower than in staff. Impaired neutralisation of delta variant spike binding was also apparent within donors without prior infection. Spike-specific T cell responses were also markedly enhanced by prior infection and within infection-naive donors were 52% lower within residents compared to staff. Post-vaccine spike-specific CD4+ T cell responses displayed single or dual production of IFN-γ+ and IL-2+ whilst previous infection primed for an extended functional profile with TNF-ɑ+ and CXCL10 production. Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naïve elderly residents of LTCF and indicate the need for further optimization of immune protection through the use of booster vaccination.

15.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295697

ABSTRACT

Background: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL) and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses.<br><br>Method: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with 2 different vaccine platforms.<br><br>Results: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n=204) or adenovirus-based (n=296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months-post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination.<br><br>Interpretation: These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoral protection against the globally-dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort.<br><br>Funding Information: This work was partially supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by DHSC/UKRI and the National Core Studies Immunity programme.<br><br>Declaration of Interests: The authors declare no conflicts of interest.<br><br>Ethics Approval Statement: Informed consent was obtained by remote consultation and work performed under the CIA UPH IRAS approval (REC 20W\0240) from North-West and Preston ethics committee and conducted according to the Declaration of Helsinki.<br>

16.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294620

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but the biological basis for this is unclear. We studied the profile of antibody and cellular immunity in children aged 3-11 years in comparison with adults. Antibody responses against spike and receptor binding domain (RBD) were high in children and seroconversion boosted antibody responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Seroneutralisation assays against alpha, beta and delta SARS-CoV-2 variants demonstrated comparable neutralising activity between children and adults. T cell responses against spike were >2-fold higher in children compared to adults and displayed a T H 1 cytokine profile. SARS-CoV-2 spike-specific T cells were also detected in many seronegative children, revealing pre-existing responses that were cross-reactive with seasonal Alpha and Beta-coronaviruses. Importantly, all children retained high antibody titres and cellular responses at 6 months after infection whilst relative antibody waning was seen in adults. Spike-specific responses in children also remained broadly stable beyond 12 months. Children thus distinctly generate robust, cross-reactive and sustained immune responses after SARS-CoV-2 infection with focussed specificity against spike protein. These observations demonstrate novel features of SARS-CoV-2-specific immune responses in children and may provide insight into their relative clinical protection. Furthermore, this information will help to guide the introduction of vaccination regimens in the paediatric population.

17.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292906

ABSTRACT

We present a comprehensive analysis of antibody and cellular responses in children aged 12-16 years who received COVID-19 vaccination with ChAdOx1 (n=6) or mRNA vaccine (mRNA-1273 or BNT162b2, n=9) using a 12-week extended-interval schedule. mRNA vaccination of seropositive children induces high antibody levels, with one dose, but a second dose is required in infection-naïve children. Following a second ChAdOx1 dose, antibody titres were higher than natural infection, but lower than mRNA vaccination. Vaccination induced live virus neutralising antibodies against Alpha, Beta and Delta variants, however, a second dose is required in infection-naïve children. We found higher T-cell responses following mRNA vaccination than ChAdOx1. Phenotyping of responses showed predominantly early effector-memory CD4 T cell populations, with a type-1 cytotoxic cytokine signature, with IL-10. These data demonstrate mRNA vaccination induces a co-ordinated superior antibody and robust cellular responses in children. Seronegative children require a prime-boost regime for optimal protection.

18.
Elife ; 102021 09 29.
Article in English | MEDLINE | ID: covidwho-1468709

ABSTRACT

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , RNA, Messenger/immunology , SARS-CoV-2/immunology , Age Factors , Aged, 80 and over , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunity, Cellular , Immunity, Humoral/immunology , Male , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods
19.
Lancet Healthy Longev ; 2(9): e554-e560, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1433992

ABSTRACT

BACKGROUND: In several countries, extended interval COVID-19 vaccination regimens are now used to accelerate population coverage, but the relative immunogenicity of different vaccines in older people remains uncertain. In this study we aimed to assess the antibody and cellular responses of older people after a single dose of either the BNT162b2 vaccine (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 vaccine (Oxford University-AstraZeneca). METHODS: Participants aged 80 years or older, who did not live in a residential or care home or require assisted living, and had received a single dose of either the BNT162b2 vaccine or ChAdOx1 nCoV-19 vaccine were eligible to participate. Participants were recruited through local primary care networks in the West Midlands, UK. Blood samples and dried blood spots were taken 5-6 weeks after vaccination to assess adaptive immune responses using Elecsys electrochemiluminescence immunoassay and cellular responses by ELISpot. Primary endpoints were percentage response and quantification of adaptive immunity. FINDINGS: Between Dec 29, 2020, and Feb 28, 2021, 165 participants were recruited and included in the analysis. 76 participants had received BNT162b2 (median age 84 years, IQR 82-89; range 80-98) and 89 had received ChAdOx1 nCoV-19 (median age 84 years, 81-87; 80-99). Antibody responses against the spike protein were detectable in 69 (93%) of 74 BNT162b2 vaccine recipients and 77 (87%) of 89 ChAdOx1 nCoV-19 vaccine recipients. Median antibody titres were of 19·3 U/mL (7·4-79·4) in the BNT162b2 vaccine recipients and 19·6 U/mL (6·1-60·0) in the ChAdOx1 nCoV-19 vaccine recipients (p=0·41). Spike protein-specific T-cell responses were observed in nine (12%) of 73 BNT162b2 vaccine recipients and 27 (31%) of 88 ChAdOx1 nCoV-19 vaccine recipients, and median responses were three-times higher in ChAdOx1 nCoV-19 vaccine recipients (24 spots per 1 × 106 peripheral blood mononuclear cells) than BNT162b2 vaccine recipients (eight spots per 1 × 106 peripheral blood mononuclear cells; p<0·0001). Humoral and cellular immune responses against spike protein were correlated in both cohorts. Evidence of previous SARS-CoV-2 infection was seen in eight participants (n=5 BNT162b2 recipients and n=3 ChAdOx1 nCoV-19 recipients), and was associated with 691-times and four-times increase in humoral and cellular immune responses across the whole cohort. INTERPRETATION: Single doses of either BNT162b2 or ChAdOx1 nCoV-19 in older people induces humoral immunity in most participants, and is markedly enhanced by previous infection. Cellular responses were weaker, but showed enhancement after the ChAdOx1 nCoV-19 vaccine at the 5-6 week timepoint. FUNDING: Medical Research Council, National Institute for Health Research, and National Core Studies.

20.
Lancet Healthy Longev ; 2(9): e544-e553, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1433991

ABSTRACT

BACKGROUND: Residents of long-term care facilities (LTCFs) have been prioritised for COVID-19 vaccination because of the high COVID-19 mortality in this population. Several countries have implemented an extended interval of up to 12 weeks between the first and second vaccine doses to increase population coverage of single-dose vaccination. We aimed to assess the magnitude and quality of adaptive immune responses following a single dose of COVID-19 vaccine in LTCF residents and staff. METHODS: From the LTCFs participating in the ongoing VIVALDI study (ISRCTN14447421), staff and residents who had received a first dose of COVID-19 vaccine (BNT162b2 [tozinameran] or ChAdOx1 nCoV-19), had pre-vaccination and post-vaccination blood samples (collected between Dec 11, 2020, and Feb 16, 2021), and could be linked to a pseudoidentifier in the COVID-19 Data Store were included in our cohort. Past infection with SARS-CoV-2 was defined on the basis of nucleocapsid-specific IgG antibodies being detected through a semiquantitative immunoassay, and participants who tested positive on this assay after but not before vaccination were excluded from the study. Processed blood samples were assessed for spike-specific immune responses, including spike-specific IgG antibody titres, T-cell responses to spike protein peptide mixes, and inhibition of ACE2 binding by spike protein from four variants of SARS-CoV-2 (the original strain as well as the B.1.1.7, B.1.351, and P.1 variants). Responses before and after vaccination were compared on the basis of age, previous infection status, role (staff or resident), and time since vaccination. FINDINGS: Our cohort comprised 124 participants from 14 LTCFs: 89 (72%) staff (median age 48 years [IQR 35·5-56]) and 35 (28%) residents (87 years [77-90]). Blood samples were collected a median 40 days (IQR 25-47; range 6-52) after vaccination. 30 (24%) participants (18 [20%] staff and 12 [34%] residents) had serological evidence of previous SARS-CoV-2 infection. All participants with previous infection had high antibody titres following vaccination that were independent of age (r s=0·076, p=0·70). In participants without evidence of previous infection, titres were negatively correlated with age (r s=-0·434, p<0·0001) and were 8·2-times lower in residents than in staff. This effect appeared to result from a kinetic delay antibody generation in older infection-naive participants, with the negative age correlation disappearing only in samples taken more than 42 days post-vaccination (r s=-0·207, p=0·20; n=40), in contrast to samples taken after 0-21 days (r s=-0·774, p=0·0043; n=12) or 22-42 days (r s=-0·437, p=0·0034; n=43). Spike-specific cellular responses were similar between older and younger participants. In infection-naive participants, antibody inhibition of ACE2 binding by spike protein from the original SARS-CoV-2 strain was negatively correlated with age (r s=-0·439, p<0·0001), and was significantly lower against spike protein from the B.1.351 variant (median inhibition 31% [14-100], p=0·010) and the P.1 variant (23% [14-97], p<0·0001) than against the original strain (58% [27-100]). By contrast, a single dose of vaccine resulted in around 100% inhibition of the spike-ACE2 interaction against all variants in people with a history of infection. INTERPRETATION: History of SARS-CoV-2 infection impacts the magnitude and quality of antibody response after a single dose of COVID-19 vaccine in LTCF residents. Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and should be considered for an early second dose where possible. FUNDING: UK Government Department of Health and Social Care.

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