cdc.gov/coronavirus

Infection-induced and hybrid immunity

Jefferson Jones, MD MPH FAAP

CDR, US Public Health Service
Shifts in vaccine-induced, infection-induced, and hybrid immunity against SARS-CoV-2 

among blood donors aged ≥16 years — United States, Quarter 2 2021– Quarter 3 2022

No infection or vaccination

Vaccine only-induced 

antibodies

Infection only-induced 

antibodies

Both infection and 

vaccination-induced 

antibodies (hybrid immunity)

Jones MMWR 2023: Data from a longitudinal, national cohort of 

>70,000 blood donors. Vaccine history is from self report. Infection 

history is based on presence of anti-nucleocapsid antibodies. 
Shifts in vaccine-induced, infection-induced, and hybrid immunity against SARS-CoV2 among people aged ≥16 years by age group — United States, Q2 2021–Q3 2022

No infection or vaccination

Vaccination without previous 

infection

Previous infection without 

vaccination

Both previous infection and 

vaccination (hybrid 

immunity)

16–29 years 30–49 years

50–64 years ≥65 years

Jones MMWR 2023: Data from a longitudinal, national 

cohort of >70,000 blood donors. Vaccine history is from 

self report. Infection history is based on presence of antinucleocapsid antibodies. 
Quantitative anti-spike antibody titers by age group 

and by infection and vaccine status, Jul-Oct 2022

Previous infection, 

unvaccinated

Previous infection, 

vaccinated

Vaccinated, no previous 

infection

Spike antibody titers (BAU/ml)

16–29 30–49 50–64 ≥65

Age (years) 

Source: CDC (unpublished). Data from nationwide blood donor cohort

Vaccine history is from self report. Infection history is based on presence of anti-nucleocapsid antibodies. 

N=2,553 N=15,437 N=27,130 N=26,034 N=3,711 N=44,486 N=21,281
63

82

89

93

0

10

20

30

40

50

60

70

80

90

100

Mar-Apr May-Jun Jul-Aug Sep-Oct Nov-Dec

Seroprevalence (%)

Month

75

85

92

97

99

0

10

20

30

40

50

60

70

80

90

100

Mar-Apr May-Jun Jul-Aug Sep-Oct Nov-Dec

Seroprevalence (%)

Month

Pediatric infection-induced and combined (vaccine- and infection-induced) 

Seroprevalence from U.S. commercial laboratories — March–December 2022

Source: https://covid.cdc.gov/covid-data-tracker/#pediatric-seroprevalence and unpublished data (CDC) Data from repeat, cross-sectional study on blood specimens collected by 

commercial laboratories. Vaccine history is unknown in this study. Infection-induced seroprevalence estimated from blood specimens tested for anti-nucleocapsid antibodies: 

the number of specimens per 2-month collection period were, by age group: 6–11 months: 157; 12–23 months: 724; 2–4 years: 2,165; 5–11 years: 9,247; and 12–17 years: 14,570. 

Combined (vaccine- and infection-induced seroprevalence estimated from specimens tested for both spike and nucleocapsid antibodies: >99% of samples tested for antinucleocapsid antibodies were tested for anti-spike antibodies. 5

Infection-induced Combined (vaccine- and infection-induced) 
Antibody titers depend more on history of infection and 

vaccination than age

6–23 month 2–4 yrs 5–11 yrs 12–17 yrs

Age group 

10000

1000

100

Spike antibody titers (BAU/ml)

Spike antibody titers (BAU/ml)

10

Previous infection, 

unvaccinated

Previous infection, 

vaccinated

Vaccinated, no 

previous infection

*Does not include specimens with no detectable antibodies

Source: CDC (unpublished)

National blood donor seroprevalence study

Ages ≥16 years, Jul–Oct 2022

National pediatric commercial lab seroprevalence study

Ages 6 months–17 years, Nov–Dec 2022, among 

specimens with antibodies*

N=612 N=1,769 N=8,299 N=13,785

N=3,711 N=44,486 N=21,281
RBD Ab levels by history of infection and vaccination 

status—children 6 mo—17+ yrs, PROTECT study

0.00

0.01

0.02

0.03

RBD AUC

6 months — 17+ years

1 infection only n=175

2 infections only n=20

1 dose only n=36

1 dose + infection only n=22

mRNA primary series only n=306

mRNA primary series + 31 infection only n=251

Booster* only n=47

Booster+ 31 infection only n=125

Antigen exposures

Blood draw within 6 months of immune modifying event, time between immune modifying events is < 365 days. 

RDB AUC: area under the curve of receptor-binding domain antibodies, a quantitative measure of binding antibodies. 

*Booster Bivalent and monovalent boosters grouped together. 

Lyski, Z and Porter, C. Unpublished data from the PROTECT cohort. PROTECT protocol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377426/
RBD Ab levels by history of infection and vaccination status 

by age group—children 6 mo—17+ yrs, PROTECT study

Immune-modifying events (in any order)

0.00

0.01

0.02

0.03

RBD AUC

6 months — <5 years

1 Infection only n=33

2 infections only n=6

1 Dose+ infection only n=4

mRNA primary series only n=13

mRNA primary series + 31 infection only n=17

Booster+ infection n=1

Antigen exposures

1 dose only n=1

Booster* only n=1

s

1 Infection only n=33

2 infections only n=6

1 Dose+ infection only n=4

mRNA primary series only n=13

mRNA primary series + 31 infection only n=17

Booster+ infection n=1

1 dose only n=1

Booster* only n=1

0.00

0.01

0.02

0.03

12-17+

RBD AUC

Antigen exposures

0.00

0.01

0.02

0.03

12-17+

RBD AUC

1 infection only n=41

2 infections only n=9

1 dose only n=12

1 dose + infection only n=5

mRNA primary series only n=125

mRNA primary series + 3 1infection only n=64

Booster* only n=16

Booster*+ 3 1 infection only n=65 0.00

0.01

0.02

0.03

RBD AUC

5-11

1 infection only n=71

dose 1 only n=23

1 dose + infection only n=15

mRNA primary series only n=169

mRNA primary series + 31 infection only n=172

Monovalent booster only n=31

Booster+ infection 31 infection only n=61

Antigen exposures

2 infections only n=10

0.00

0.01

0.02

0.03

RBD AUC

5-11

1 infection only n=71

dose 1 only n=23

1 dose + infection only n=15

mRNA primary series only n=169

mRNA primary series + 31 infection only n=172

Monovalent booster only n=31

Booster+ infection 31 infection only n=61

2 infections only n=10

n= 72 n= 552 n= 337
SARS-CoV-2 neutralizing antibody (nAb) studies

▪ In unvaccinated persons, infection-induced nAb titers highest against variants 

similar to the variant that infected the person1

▪ nAb titers in people with hybrid immunity may wane slower than in 

people vaccinated without infection2

– Infection after vaccination may be moderated by imprinting3

▪ Omicron

– Omicron variants demonstrate greater escape from neutralization than older 

variants1–2,4–6

– Additional vaccine doses beyond primary series increase Omicron nAb titers4,5

– Hybrid immunity results in higher Omicron nAb titers than immunity from 

infection or vaccination alone, including to recent Omicron subvariants4

1 Rössler 2022 NEJM; 2 Qu 2022 NEJM; 3 Wheatley Trends Immunol 2021; 4 Kurhade 2023 Nat Med; 

5 Gaebler 2022 OFID; 6 Barateau 2023 Sci Transl Med
Other SARS-CoV-2 immunity laboratory study highlights

▪ Hybrid immunity appears to result in stronger more robust immune response 

using other measures as well, including

– Infection-induced and hybrid immunity result in higher IgA titers than 

vaccine-induced immunity1,2

– Hybrid immunity may result in higher proportion of anti-spike memory 

B cells than vaccination alone3

– Hybrid immunity induces T cells and antibodies directed against nonspike viral antigens4

▪ T-cell immunity from both infection and vaccination well preserved against 

Omicron4

– Cellular immunity likely important in preventing severe disease5

1 Barateau 2023 Sci Transl Med; 2 Sheikh-Mohamed Immunol Rev 2022; 

3 Bednarski 2022 mBio; 4 Naranbhai 2022 Cell ; 5 Moss 2022 Nature
Systematic review of protection against Omicron from infection, hybrid with 

monovalent primary series, and hybrid with first monovalent booster

Bobrovitz 2023 Lancet
Conclusions

▪ SARS-CoV-2 infection can cause severe disease, death, and long-term morbidity, whereas COVID-19 

vaccination is safe and effective at preventing severe COVID-19 disease

▪ The proportion of people with immunity from infection or hybrid immunity has increased

▪ Immunity following vaccination and infection wanes over time, and both monovalent primary series 

vaccination and history of pre-Omicron infection provided much lower protection during Omicron than 

during prior COVID-19 waves

▪ Compared with protection from infection or vaccination alone, hybrid immunity likely better protects 

against infection and severe disease with Omicron

▪ Stronger protection is likely provided when the infecting variant is similar to the circulating variant, but this 

may be complicated by imprinting

▪ Current protection likely influenced by both cumulative number of vaccine doses, number of times 

infected, and timing of most recent vaccination or infection, and how closely the circulating variant 

matches the vaccine or prior infection

▪ Conclusions apply to both children and adults
Acknowledgments

▪ Tarayn Fairlie

▪ Melissa Briggs-Hagen

▪ Melissa Coughlin

▪ Natalie Thornburg

▪ Claire Midgley

▪ Ian Plumb

▪ Amadea Britton

▪ Ruth Link-Gelles

▪ Amanda Payne

▪ PROTECT team
For more information, contact CDC

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TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.