Credit CDC/ACIP
#16,566
One of the issues raised very early in the COVID pandemic concerned the durability of immunity, gained either from infection, or from a (at that time, nonexistent) vaccine. While data was limited, coronaviruses had a `reputation' of provoking a less-than-robust immune response.
In Fenner and White's Medical Virology (Fifth Edition - 2017), the authors describe the clinical features of seasonal human coronaviruses (hCoVs) in Chapter 31:
The typical coronavirus “common cold” is mild and the virus remains localized to the epithelium of the upper respiratory tract and elicits a poor immune response, hence the high rate of reinfection. There is no cross-immunity between human coronavirus-229E and human coronavirus-OC43, and it is likely that new strains are continually arising by mutation selection.
In 2016's EID Journal: Antibody Response & Disease Severity In HCW MERS Survivors, we looked at a study that tested 9 Health care workers who were infected during the 2014 Jeddah outbreak (2 severe pneumonia, 3 milder pneumonia, 1 URTI, and 3 asymptomatic), that found only those with severe pneumonia still carried detectable levels of antibodies 18 months later.
Those who experienced a milder pneumonia had shorter lived antibody responses (1 out to 10 months, 2 out to 3 months), while the URTI and asymptomatic cases tested negative at 3 months post infection.
We explored these barriers to `herd immunity' frequently in the spring and summer of 2020 (see COVID-19: From Here To Immunity and GAO: A Herd Immunity For COVID-19 Primer) while we awaited signs of confirmed reinfection with SARS-CoV-2.
By the end of summer we were beginning to see clear evidence of reinfections (see HKU Med Announces 1st Documented Reinfection With SARS-CoV-2), and warnings - even before the first major variants emerged - that acquired immunity was likely temporary.In October 2020 - two months before the first vaccines rolled out - in A COVID Vaccine Reality Check, we looked at the risks of `over-selling' the vaccine, and I cautioned that even a moderately successful vaccine would be viewed as a failure if it was sufficiently over-hyped.
Fast forward a little over a year, and the much ballyhooed 95% protection against infection initially offered by the mRNA vaccines has eroded significantly.
The vaccine still offers significant protection against severe disease, hospitalization, and death - but it's protection against `breakthrough' infection (even when boosted), wanes over time.
And with the emergence and spread of new variants (Alpha, Delta, Omicron, etc.), the virus has strayed further antigenically from the original vaccine's target, lowering the vaccine's effectiveness even more.
None of this makes the vaccine a `failure' - as it has undoubtedly saved millions of lives - but it reminds us that even successful vaccines have limits.
Which brings us to a new MMWR report, published yesterday, that looks at the effectiveness of 2 and 3 dose mRNA vaccines against more serious COVID illness (ER & UC visits, hospitalizations) over time.
The very good news is that getting the booster shot increased VE (vaccine effectiveness) against ER/UC visits and hospitalizations over getting the second shot - and VEs were generally high - but they do decline over time.
Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022
Early Release / February 11, 2022 / 71
Jill M. Ferdinands, PhD1; Suchitra Rao, MBBS2; Brian E. Dixon, PhD3,4; Patrick K. Mitchell, ScD5; Malini B. DeSilva, MD6; Stephanie A. Irving, MHS7; Ned Lewis, MPH8; Karthik Natarajan, PhD9,10; Edward Stenehjem, MD11; Shaun J. Grannis, MD3,12; Jungmi Han9; Charlene McEvoy, MD6; Toan C. Ong, PhD2; Allison L. Naleway, PhD7; Sarah E. Reese, PhD5; Peter J. Embi, MD3,12,13; Kristin Dascomb, MD11; Nicola P. Klein, MD8; Eric P. Griggs, MPH1; Deepika Konatham14; Anupam B. Kharbanda, MD15; Duck-Hye Yang, PhD5; William F. Fadel, PhD3,4; Nancy Grisel, MPP11; Kristin Goddard, MPH8; Palak Patel, MBBS1; I-Chia Liao, MPH14; Rebecca Birch, MPH5; Nimish R. Valvi, DrPH3; Sue Reynolds, PhD1; Julie Arndorfer, MPH11; Ousseny Zerbo, PhD8; Monica Dickerson1; Kempapura Murthy, MBBS14; Jeremiah Williams, MPH1; Catherine H. Bozio, PhD1; Lenee Blanton, MPH1; Jennifer R. Verani, MD1; Stephanie J. Schrag, DPhil1; Alexandra F. Dalton, PhD1; Mehiret H. Wondimu, MPH1; Ruth Link-Gelles, PhD1; Eduardo Azziz-Baumgartner, MD1; Michelle A. Barron, MD2; Manjusha Gaglani, MBBS14,16; Mark G. Thompson, PhD1; Bruce Fireman8 (View author affiliations)View suggested citation
Summary
What is already known about this topic?
Protection against COVID-19 after 2 doses of mRNA vaccine wanes, but little is known about durability of protection after 3 doses.
What is added by this report?
Vaccine effectiveness (VE) against COVID-19–associated emergency department/urgent care (ED/UC) visits and hospitalizations was higher after the third dose than after the second dose but waned with time since vaccination. During the Omicron-predominant period, VE against COVID-19–associated ED/UC visits and hospitalizations was 87% and 91%, respectively, during the 2 months after a third dose and decreased to 66% and 78% by the fourth month after a third dose. Protection against hospitalizations exceeded that against ED/UC visits.
What are the implications for public health practice?
All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19–associated hospitalizations and ED/UC visits.
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CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1–5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance.
A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).¶
Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021–January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination.
During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4–5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose.
For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19–associated hospitalizations and ED/UC visits.
(SNIP)
Discussion
In a multistate analysis of 241,204 ED/UC encounters and 93,408 hospitalizations among adults with COVID-19–like illness during August 26, 2021–January 22, 2022, estimates of VE against laboratory-confirmed COVID-19 were lower during the Omicron-predominant than during the Delta-predominant period, after accounting for both number of vaccine doses received and time since vaccination. During both periods, VE after receipt of a third dose was always higher than VE following a second dose; however, VE waned with increasing time since vaccination.
During the Omicron-predominant period, mRNA vaccination was highly effective against both COVID-19–associated ED/UC encounters (VE = 87%) and COVID-19 hospitalizations (VE = 91%) within 2 months after a third dose, but effectiveness waned, declining to 66% for prevention of COVID-19–associated ED/UC encounters by the fourth month after receipt of a third dose and to 78% for hospitalizations by the fourth month after receipt of a third dose. The finding of lower VE for 2 or 3 doses during the Omicron-predominant period is consistent with previous reports from the VISION network and others¶¶¶,**** (2,7). Waning of VE after receipt of a third dose of mRNA vaccine has also been observed in Israel (8) and in preliminary reports from the VISION Network (2).
This analysis enhances an earlier VISION Network report (2) by extending the Omicron study period to January 22, 2022, providing a more detailed breakdown of time since vaccination, and using an analytic technique that better controls for potential confounding by calendar week and geographic area. By comparing COVID-19 test-positive case-patients with COVID-19 test-negative control patients in the same geographic area and for whom encounter index dates occurred within the same week, bias in VE estimates resulting from temporal and spatial variations in virus circulation and vaccine coverage was reduced.
The findings in this report are subject to at least seven limitations.
- First, because this study was designed to estimate VE against COVID-19–associated ED/UC visits or hospitalizations, VE estimates from this study do not include COVID-19 infections that were not medically attended.
- Second, the median interval from receipt of a third dose to medical encounters was 49 days; thus, the observed performance of a third dose is limited to a relatively short period after vaccination.
- Third, the small number of COVID-19 test-positive patients in the most remote time-since-vaccination groups reduced the precision of the VE estimates for those groups (e.g., ≥5 months).
- Fourth, variations in waning of VE by age group, immunocompromised status, other indicators of underlying health status, or vaccine product have not yet been examined. This study could not distinguish whether a third dose was received as an additional dose as part of a primary series (as recommended for immunocompromised persons) or as a booster dose after completion of a primary series. Further research should evaluate waning VE of a third primary dose among immunocompromised adults compared with waning of VE after a booster dose among immunocompetent adults.
- Fifth, despite adjustments to account for differences between unvaccinated and vaccinated persons, VE estimates might have been biased by residual differences between these groups with respect to immunocompromised status and other health conditions, as well as from unmeasured behaviors (e.g., mask use and close contact with persons with COVID-19). For example, insufficient adjustment for immunocompromised status might have biased the estimates of VE downward among persons most remote from receipt of a third dose.
- Sixth, genetic characterization of patients’ viruses was not available, and analyses relied on dates when the Omicron variant became locally predominant based on surveillance data; therefore, the Omicron period of predominance in this study likely includes some medical encounters associated with the Delta variant.
- Finally, although the facilities in this study serve heterogeneous populations in 10 states, the findings might not be generalizable to the U.S. population.
These findings underscore the importance of receiving a third dose of mRNA COVID-19 vaccine to prevent both COVID-19–associated ED/UC encounters and COVID-19 hospitalizations among adults. The finding that protection conferred by mRNA vaccines waned in the months after receipt of a third vaccine dose reinforces the importance of further consideration of additional doses to sustain or improve protection against COVID-19–associated ED/UC encounters and COVID-19 hospitalizations. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19–associated hospitalizations and ED/UC visits.
While the mRNA vaccines may not live up to the original hype, they still do a good job in reducing morbidity and mortality from currently circulating COVID variants, and I'm personally grateful for the protection they've provided me.
But COVID continues to mutate and evolve, and as we explored last summer in UK SAGE: Can We Predict the Limits of SARS-CoV-2 Variants and their Phenotypic Consequences?, existing vaccines and therapeutics will likely continue to lose effectiveness, and will eventually need to be updated or replaced.
Like it or not, we are in an `arms race' with a highly mutable virus. And that will require a certain degree of nimbleness on our part going forward.
