The COV-BOOST study evaluated the immune response to different heterologous COVID-19 vaccine boosters. It found that all boosters, except the Valneva vaccine after a Pfizer primary series, increased antibody levels and neutralization compared to baseline. mRNA vaccines like Pfizer and Moderna boosted antibodies more than AstraZeneca or Novavax, which boosted more than adenovirus vector vaccines as a booster. Reactogenicity was generally higher for Moderna and CureVac boosters and adenovirus vector boosters after a Pfizer primary series. While the study provides data on immune responses, the clinical effectiveness of these booster combinations still needs validation through outcomes like infections and disease severity.

1. Virtual Journal Club #1
Heterologous Boosters:
“Mix and Match”?
COV-BOOST study: Munro et al. Lancet 2021(Dec 18/25); 398: 2258–76
Benjamin P. Geisler, M.D., M.P.H., F.A.C.P., M.R.C.P. (London), F.H.M.
Massachusetts General Hospital/Harvard Medical School

3. Journal Club, Bayesian-style?
• What was known before the
study?
• Are the results of the new study
in line with what we expected?
• Given how rigorous (or not) the
methods were, can the results
be trusted?
• So what? Does this change our
thinking?

4. Outline
• What Was Known Before the Study?
• What Was the Study Goal?
• Which Combos of Boosters and Primary Series Were Studied?
• Methods
• (Some) baseline characteristics
• Results – Antibody and T-cell concentrations
• Results – AEs
• Critical Appraisal
• What Has Been Published Since?
• Discussion

5. What Was Known Before the Study?
• COM-COV RCT and other studies
demonstrated formal non-inferiority
but still much higher responses of
Pfizer/BioNTech as a second dose
after AstraZeneca/Oxford
• Three published booster trials
• Two preprints
• Neutralizing antibody titers
significantly ↑ after a homologous
AstraZeneca/Oxford, Pfizer/BioNTech,
or Moderna/NIH booster
• This was only true for the delta variant
for Pfizer/BioNTech and Moderna/NIH
• A pre-print also confirmed a good
neutralizing AB response after a
heterologous booster
• T-cell response was good after
AstraZeneca/Oxford, and not reported
for the others
• Reactogenicity similar to initial series,
except ↑ for Convidecia andCoronaVac

7. What Was the Study Goal? Endpoints?
• Phase II study
• Biological activity
(or prelim. efficacy)
• Safety
→Anti-spike IgG at 28d
→Ratios compared to pre-booster
→Absolute titers
→Neutralizing Abs (against wild-type)
→Pseudoviral neutralization
→T-cell response
→Adverse events
→Unsolicited
→Solicited
→Serious
Immunogenicity
Reactogenicity

8. Which Combos of Boosters and Primary
Series Were Studied?
Boosters Studied Here
• ChAdOx1 nCov-19
(Oxford/AstraZeneca): ChA
• BNT162b2 (Pfizer/BioNtech): BNT
• mRNA1273 (Moderna/NIH):
m1273 (100 μg only)
• COV2.S (Janssen/J&J): Ad26
• CVnCov (CureVac): CVn
• NVX-CoV2373 (Novavax): NVX
• Full/half VLA2001 (Valneva): VLV
What Was Not Studied
• No primary series other than ChA
or BNT studied
• NBs:
• Some Western countries also had
more and more m1273 over time (the
U.S. had a lot from the beginning)
• Ad26 use was high in the U.S. but ↓
• m1273 booster was reduced to 50 μg
• FDA never approved ChA
• Pivotal CVn trial failed
• NVX has only recently been approved
• Sputnik V? Convidecia/CoronaVac?

9. Which Combos of Boosters and Primary
Series Were Studied?
Booster Primary Series ChA BNT
ChA
BNT full
BNT half
m1273 (100 μg)
Ad26
CVn
NVX full
NVX half
VLV full
VLV half
Active controls

10. Which Combos of Boosters and Primary
Series Were Studied?
Booster Primary Series ChA BNT
ChA ChA after primary ChA series ChA after primary BNT series
BNT full BNT full after primary ChA series BNT after primary BNT series
BNT half BNT half after primary ChA series BNT half after primary BNT series
m1273 (100 μg) m1273 after primary ChA series m1273 after primary BNT series
Ad26 Ad26 after primary ChA series Ad26 after primary BNT series
CVn CVn after primary ChA series CVn after primary BNT series
NVX full NVX full after primary ChA series NVX full after primary BNT series
NVX half NVX half after primary ChA series NVX half after primary BNT series
VLV full VLV full after primary ChA series VLV full after primary BNT series
VLV half VLV half after primary ChA series VLV half after primary BNT series
Active controls Active contr. after prim. ChA series Active contr. after prim. BNT series

11. Which Combos of Boosters and Primary
Series Were Studied?
Booster Primary Series ChA BNT
ChA ChA after primary ChA series ChA after primary BNT series
BNT full BNT full after primary ChA series BNT after primary BNT series
BNT half BNT half after primary ChA series BNT half after primary BNT series
m1273 (100 μg) m1273 after primary ChA series m1273 after primary BNT series
Ad26 Ad26 after primary ChA series Ad26 after primary BNT series
CVn CVn after primary ChA series CVn after primary BNT series
NVX full NVX full after primary ChA series NVX full after primary BNT series
NVX half NVX half after primary ChA series NVX half after primary BNT series
VLV full VLV full after primary ChA series VLV full after primary BNT series
VLV half VLV half after primary ChA series VLV half after primary BNT series
Active controls Active contr. after prim. ChA series Active contr. after prim. BNT series

13. Methods
• Double-blind, multi-center (-centre?) RCT
• Randomization with permutated random blocks in REDCap
• Controls were a quadrivalent meningococcal vaccine (MenACWY by Pfizer)
• Participants >30y w/ no or mild-mod, well-controlled comorbidities
• Clinicians, participants, and statisticians were all blinded
• Vaccines were prepared “out of sight” and masking tape was applied to the
syringes to conceal dose, volume, and appearance
• Blood was taken at day 28 (additional blood draws at d84, d365, and for
subgroup at d7 and d14)
• ELISA (for anti-spike IgG titers)
• SARS-CoV-2 pseudotype virus neutralization assays (PNAs)
• T-cell assays

14. Results – (Some) Baseline Characteristics

16. Results – Enrollement

17. Results – Antibody and T-cell concentrations

18. ChAd-primed

19. BNT-primed
BNT-primed

20. ChAd-primed

21. BNT-primed

22. 0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000
ChAD BNT BNT half m1273 Ad26 CVn NVX NVX half VLA VLA half
ChAd-primed <70
Mean anti-spike IgG ELU/ml

23. ChAD primary <70
ChAD primary ≥70
BNT primary <70
BNT primary ≥70
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
ChAD BNT BNT half m1273 Ad26 CVn NVX NVX half VLA VLA half
ChAD primary <70 ChAD primary ≥70 BNT primary <70 BNT primary ≥70
Mean anti-spike IgG ELU/ml

24. Results – Severe and Solicited AEs

25. Results – Moderate/Severe Solicited AEs

26. Results – Moderate/Severe Solicited AEs

27. Results – Moderate/Severe Solicited AEs

28. Results Summary/Conclusion
• All vaccines (except VLA after BNT) boosted antibodies & neutralized
• Substantial differences in humoral and cellular responses (as well as
vaccine availability) will influence policy choices

29. Results Summary/Conclusion
• All vaccines (except VLA after BNT) boosted antibodies & neutralized
• Substantial differences in humoral and cellular responses (as well as
vaccine availability) will influence policy choices
• Antibody levels were boosted more by mRNA vaccines than AV ones,
with NVX somewhere in the middle
• Reactogenicity was higher for m1273 and CVn (but not BNT) for any
primary series, and for ChAd and Ad26 (the two adenovector
vaccines) for the BNT-primed

30. Critical Appraisal
• Overall well-conducted double-blind RCT
• Methods description is brief but adequate; only concern is how far out of
sight (and by whom) the vaccine doses were prepared before concealment
• Only healthy participants or those w/ mild/mod, wel-contr. comorbidities
• Available primary series at the time in other parts of the world (m1273,
Ad26, Sputnik V, Convidecia, CoronaVac) were not trialed
• The dose of m1273 has since been halved in reaction to its reactogenicity
• Antibody and T-cell responses have not been validated to hard endpoints
(infections, severe disease, admission, intubation/ventilation, death)

31. What Has Been Published Since?

32. What Has Been Published Since?

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40. What Has Been Published Since?

41. Discussion