A Methodological Framework for Assessing the Benefit of SARS-CoV-2 Vaccination following Previous Infection: Case Study of Five- to Eleven-Year-Olds
2.1. Quantifying the Additional Benefit of Vaccination for an Individual Previously Infected Child
2.2. Incorporating Waning
2.4. Estimating Additional Benefit for the Six Months Post-Vaccination following Previous Infection with Linear-Approximated Waning
2.5. Parameterising the Framework and Depicting Plausible Benefit
3.1. Hospital Admissions Averted
3.2. Cases of Long Covid Averted
4.2. Strengths and Limitations
4.3. Policy Implications
4.4. Future Research
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Adverse outcome of type due to infection|
|Adverse outcome of type due to vaccination|
|Time of a child’s most recent infection|
|Time of vaccination|
|Time of maximal vaccination efficacy in weeks (while Lin et al. show good effectiveness by two weeks, their reported maximal efficacy is at four weeks, after which waning begins )|
|Time between last infection and four weeks after vaccination (), where this is at least 16 weeks (allowing 12 weeks between infection and vaccination, as per current UK guidance)|
|Time since four weeks after vaccination|
|The degree of protection afforded by previous infection against adverse outcome of type at time after infection in an unvaccinated child. Protection can range from 0 (no protection) to 1 (complete protection)|
|The degree of protection afforded by vaccination after previous infection against adverse outcome of type at time after administration + four weeks (to allow for maximum efficacy). Protection can range from (same as previous infection alone) to 1 (complete protection)|
|Probability of adverse event of type for a child infected for the first time|
|Probability of adverse event of type due to the vaccine|
|The number of adverse events of type caused by the vaccine if the whole population of children were vaccinated|
|Number of adverse events of type across the whole population of children, if all infected for the first time|
|Number of adverse events of type due to the vaccine across the whole population of children, if all vaccinated|
|The proportion of children infected (again) in the future, over some time period, where the proportion can range from 0 (no new infections) to 1 (all children reinfected)|
|The rate of waning of protection following infection or vaccination following infection, respectively|
|Parameter for Children Aged 5 to 11||Value for Those with UHC||Value for Those with no UHC||Comment (Further Detail Provided in Supplementary Materials)|
|Number in population resident in England||687,935||4,036,891||We use 2021 UK Office for National Statistics (ONS) estimates for overall population of 5–11-year-olds . We derive a UHC rate of 14.6% based on the proportion of medical records for all of the five- to eleven-year-olds in the NHS Digital Trusted Research Environment where there was evidence of a health condition linked to greater vulnerability to severe disease with SARS-CoV-2 infection by the JCVI  as per the method described in Wilde et al. (under review) . This rate is then applied to the overall ONS population estimate.|
|Proportion infected at least once by March 2022||82%||We use the UK Office for National Statistics (ONS) Schools Infection Survey antibody study for primary school children from early 2022 reporting that 82% of primary-school-age children had antibodies. The actual proportion infected is likely to be much higher (ONS infection survey estimates cumulative incidence of 123% by March 2022 ), so this is a conservative estimate. We assume the same proportion for children with UHC and those without UHC since we do not have a reliable way of estimating difference in infection likelihood between the two populations.|
|Number of hospital admissions directly associated with first ascertained SARS-CoV-2 infection July 2020 to end February 2022||3375||3465||We use the number reported in Wilde et al. (under review)  for first hospital admissions associated with first ascertained SARS-CoV-2 infection in children aged five to eleven and excluding admissions that are incidental to SARS-CoV-2 infection (see Wilde et al. for details), from July 2020 to end of February 2022 in England.|
NOTE: this will be an underestimate of all hospitalisations since it excludes individuals that had an admission prior to July 2020.
|Number of hospital admissions expected if whole population had been infected for the first time ()||4120||4230||Obtained by dividing the number observed by the proportion of children infected in each group as given in row 2 above, to three significant figures.|
|Maximum protection of previous infection against hospitalisation from reinfection )||99.5%||Lin et al.  give an estimate of 99.5% efficacy at 1 month post-infection against hospitalisation.|
|Maximum protection of vaccination in children with previous infection (at least 16 weeks after infection and 4 weeks after vaccination) )||100%||Lin et al.  do not provide estimates for additional protection from vaccination but just say that it is higher than vaccination or infection alone. Bobrovitz et al.  give an efficacy of over 95% at both three and twelve months after two or three doses of vaccine following infection.|
|The waning rate of protection from either vaccination following infection or infection alone ()||1.3 percentage points per month (minimum 0.6 and maximum 1.7)||Estimated using the data in the supplemental material for Lin et al.  for protection from previous Omicron infection only. See Supplementary Materials for fits for maximum and minimum ranges and Figure 2 for the central estimate.|
|The number of hospitalisations due to vaccine adverse events if all children were vaccinated (NVA)||1||7||A systematic review of vaccination for 5–11-year-olds reported a myocarditis rate of 1.3–1.8/million vaccinations given . Extrapolating this rate to the five to eleven year old population in UK (five million) and conservatively assuming all would be hospitalised gives a central estimate of eight hospital admissions due to the vaccine, which we split across UHC and non UHC children 1:7. We note that Watanabe et al. report no vaccine-caused deaths among 16.6 million injections .|
|Attack Rate (Proportion of Children Reinfected in the 6 Months Post-Vaccination)||Estimated Number of Hospitalisations Averted on Reinfection if All 4 Million Children without Underlying Health Conditions (UHC) Were Vaccinated on Average a Year after Previous Infection||Estimated Number of New Cases of Long Covid Averted on Reinfection if All 4.7 Million Children Were Vaccinated on Average a Year after Previous Infection|
|5%||25 (10–35)||3500 (800–6500)|
|25%||160 (75–215)||18,000 (4000–32,000)|
|40%||265 (120–350)||29,000 (6500–51,000)|
|50% (ONS estimate an incidence rate of 45% in 2- to 11-year-olds July–December 2022)||330 (160–440)||36,500 (8000–64,000)|
|60%||400 (190–520)||43,500 (9500–76,500)|
|75%||500 (240–660)||54,500 (12,000–96,000)|
|95% (ONS estimate an incidence rate of 98% in 2- to 11-year-olds, Dec 2021 to June 2022)||640 (300–830)||69,000 (15,000–121,500)|
|Parameter for Children Aged Five to Eleven||Value||Comment|
|Number in population resident in England||4,724,826||We use 2021 UK Office for National Statistics (ONS) estimates for overall population of five- to eleven-year-olds .|
|Incidence of Long Covid (ongoing symptoms lasting at least 3 months following first infection)||3.5%||A central estimate from recent studies and the American Academy of Pediatrics [47,48,49,50].|
|Number of children experiencing Long Covid if whole population had been infected for the first time ()||165,000||Rounded to three significant figures.|
|(Infection only): Protection of previous infection against new Omicron infection at one year post-infection (representing )||16–36%||Bobrovitz et al.  give an efficacy of 24.7% at 12 months with CI 16.4% to 35.5%.|
|Hybrid): Maximum protection against reinfection of vaccination in children following previous infection. We are interested in efficacy just after vaccination )||59–78%||Bobrovitz et al.  give an efficacy of 69.0% at 3 months with CI 58.9% to 77.5%, and we use this as a conservative estimate of maximum vaccine benefit following previous infection. Note also that Dowell et al.  show that antibodies to SARS-CoV-2 are increased greatly in children with vaccination on top of previous immunity (from Omicron).|
|(Infection only): Minimum and maximum protection of previous infection against Long Covid once reinfected at least one year later||0–40%||There is a great deal of uncertainty in the protection afforded by previous infection once reinfected. The UK ONS reports no significant difference in reporting Long Covid in 2- to 11-year-olds 20 weeks after reinfection vs. 20 weeks after first infection . We choose a range of 0–40% as a plausible range.|
|(Hybrid): Maximum protection of vaccination following previous infection against Long Covid once reinfected||30–70%||There is a great deal of uncertainty in the protection afforded by hybrid immunity once reinfected. Protection from vaccination alone is thought to be somewhere between 15–50% . A recent systematic review reported great uncertainty in the scale but likely definite benefit of vaccination in preventing Long Covid . Assuming hybrid protection is better than vaccination alone, we chose a range of 30–70%.|
|Overall effectiveness of previous infection one year earlier against new Long Covid on reinfection||16–62%||Combining minimum and maximum ranges of respective protections above.|
|Overall effectiveness of vaccination after previous infection against new Long Covid on reinfection||71–93%||Combining minimum and maximum ranges of respective protections above.|
|The number of Long Covid cases due to vaccination if all children were vaccinated||0||There is no mechanism by which vaccination can cause Long Covid.|
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Pagel, C.; Wilde, H.; Tomlinson, C.; Mateen, B.; Brown, K. A Methodological Framework for Assessing the Benefit of SARS-CoV-2 Vaccination following Previous Infection: Case Study of Five- to Eleven-Year-Olds. Vaccines 2023, 11, 988. https://doi.org/10.3390/vaccines11050988
Pagel C, Wilde H, Tomlinson C, Mateen B, Brown K. A Methodological Framework for Assessing the Benefit of SARS-CoV-2 Vaccination following Previous Infection: Case Study of Five- to Eleven-Year-Olds. Vaccines. 2023; 11(5):988. https://doi.org/10.3390/vaccines11050988Chicago/Turabian Style
Pagel, Christina, Harrison Wilde, Christopher Tomlinson, Bilal Mateen, and Katherine Brown. 2023. "A Methodological Framework for Assessing the Benefit of SARS-CoV-2 Vaccination following Previous Infection: Case Study of Five- to Eleven-Year-Olds" Vaccines 11, no. 5: 988. https://doi.org/10.3390/vaccines11050988