COVID-19 Reinfection and the Importance of Maintaining Proper Vaccination Status

Phyllis Tien, MD, is a professor of medicine in the Division of Infectious Diseases at the University of California, San Francisco, and a staff physician at the San Francisco Veterans Affairs Health Care System. Dr Tien serves as chair of the Inter-CFAR Collaboration on HIV Research in Women and is currently a member of the National Institutes of Health COVID-19 Treatment Guidelines panel.

In one study, experts compared different booster vaccines by measuring neutralizing antibody responses, seroresponse, and binding antibody responses against multiple variants, all of which served as biomarkers for efficacy.¹ Can you explain how those data translate to preventing COVID-19 infection in the general public?

Neutralizing antibodies, seroresponse, and binding antibodies can be considered as surrogate markers of whether a vaccine is effective in preventing severe disease, hospitalization, and death. It would be incredibly difficult to perform a large-scale randomized controlled trial (RCT) to determine true vaccine efficacy by use of clinical outcomes. This is especially true when the virus keeps mutating into different variants against which some vaccines may be less effective. Instead, to compare vaccines, like a booster bivalent dose with a booster monovalent dose, we have to rely on assessing their effects on neutralizing antibodies, binding antibodies, and seroresponse.
 
There are no standardized correlations between antibody titer cutoffs and clinical outcomes because laboratories use different assays or ways to measure antibody titers. Within the context of an RCT, however, being able to compare antibody titers between groups can be informative and helps us to put these numbers into perspective in terms of vaccine effectiveness.

Several cohort studies have demonstrated that COVID-19 immunity decreases with time after immunization.^2-4 How does the administration of either a monovalent or a bivalent vaccine affect the durability of protection received by COVID-19 vaccination?

It is difficult to address the durability of vaccine response given the rapidly emerging immune-evasive variants. The results of cohort studies indicate that booster vaccine doses are associated with a reduced risk for COVID-19 infection, hospitalization, and death. In that sense, booster vaccine doses extend the durability of protection.

Is there a perceived benefit to administering a booster dose of the bivalent COVID-19 vaccine in patients who have already received multiple doses of a monovalent COVID-19 vaccine?

The bivalent Omicron-containing booster vaccine study presented in the New England Journal of Medicine suggests that, by use of neutralizing antibodies and binding antibodies as an endpoint, there is a benefit to using the bivalent mRNA-1273.214 vaccine over the monovalent mRNA-1273 vaccine in terms of raising antibody titers.¹
 
Participants in the study had received a primary vaccine series and a monovalent mRNA-1273 COVID-19 booster. Thus, we are seeing higher immune antibody responses in people given the bivalent booster vaccine, even in patients who had previously received a booster dose of the monovalent mRNA-1273 COVID-19 vaccine.

Can you elaborate on the effectiveness of COVID-19 vaccination in preventing various clinical outcomes, such as COVID-19 reinfection, hospitalization, or death?

The Centers for Disease Control and Prevention (CDC) COVID data tracker suggests that hospitalizations and deaths are lower now than earlier in the pandemic.⁵ Large cohort studies, notably the Veterans Affairs study³ and a study from North Carolina,⁴ confirm that COVID-19 vaccination, including booster doses, is contributing to the decline in new cases of severe COVID-19.
 
The greatest decreases are in hospitalization and death. When using a database for a cohort study, it is easier to assess whether a patient has been hospitalized or has died. Those hard endpoints are showing that COVID-19 vaccines are effective. With COVID-19 infection and reinfection, the data can be more difficult to quantify. A patient may have completed an antigen test at home, whereas someone else who is sicker may get tested at a facility. It is also possible that patients who have received a booster vaccine dose are more likely to be tested for COVID-19 infection. With so many confounders, we may not see the effect of vaccination on COVID-19 infection that we would prefer.

In another study, the neutralizing antibody response of the bivalent V-01D-351 booster was shown to be durable for at least 90 days after administration.⁶ Given these and other supporting data on the durability of boosters for maintaining immunity against COVID-19, how do you counsel patients on the need for repeat vaccinations, especially those who may have already received a monovalent booster dose?

Currently, the CDC is recommending a bivalent booster dose 2 months after the last dose of COVID-19 vaccine.⁷ When booster doses were first recommended, patients were asked to wait 5 months after the previous COVID-19 vaccination. Some patients are confused because the recommendations are changing. This is not uncommon in a pandemic because recommendations change as new information about the virus emerges, such as new variants that appear to be more immune-evasive. These are considerations that contribute to why the interval has been shortened. I tell my patients that the purpose of booster doses is to prevent hospitalization and death from COVID-19.
 
The frequency of vaccination may also be related to the type of vaccine that we are using — for example, an mRNA or a subunit protein vaccine. Some of our traditional subunit vaccines do not need to be repeated frequently only because of the durability of response. However, it takes time to develop the “right” type of vaccine that can elicit a longer durable response.

Some patients experience breakthrough COVID-19 infection as well as reinfection. Can you elaborate on the need for booster vaccination in this subset of patients as well as provide some insight into the timing (ie, when patients should follow up with their health care provider to receive the booster)?

I receive this question a lot, especially because so many patients were infected with the Omicron variant in the summer of 2022. Natural infection does lead to a nice immune response and has a synergistic effect with the bivalent COVID-19 vaccine.¹ In the study comparing the bivalent booster with the monovalent booster, vaccination with the bivalent booster led to an increase in neutralizing antibodies even in study participants with prior SARS-CoV-2 infection, and neutralizing antibody levels appeared to be higher in participants who had a previous SARS-CoV-2 infection than in those who had not been infected with SARS-CoV-2.¹
 
The CDC states that you could consider delaying your primary or booster vaccine dose by 3 months from the onset of your symptoms or a positive test result if you are asymptomatic.⁸ With the recommendation for people to receive the bivalent booster 2 months from the previous vaccine dose, a good general rule for when to get the COVID-19 vaccine booster seems to be 2 to 3 months after infection.

This Q&A was edited for clarity and length.

Disclosures

Phyllis Tien, MD, reported affiliations with Merck & Co, Inc.

References

1. Chalkias S, Harper C, Vrbicky K, et al. A bivalent Omicron-containing booster vaccine against COVID-19. N Engl J Med. 2022;387:1279-1291. doi:10.1056/NEJMoa2208343
 
2. Berec L, Smid M, Pribylova L, et al. Protection provided by vaccination, booster doses and previous infection against COVID-19 infection, hospitalisation or death over time in Czechia. PLOS One. 2022;17(7):e0270801. doi:10.1371/journal.pone.0270801
 
3. Kelly JD, Leonard S, Hoggatt KJ, et al. Incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines. JAMA. 2022;328(14):1427-1437. doi:10.1001/jama.2022.17985
 
4. Lin D-Y, Gu Y, Xu Y, et al. Association of primary and booster vaccination and prior infection with SARS-CoV-2 infection and severe COVID-19 outcomes. JAMA. 2022;328(14):1415-1426. doi:10.1001/jama.2022.17876
 
5. COVID data tracker. Centers for Disease Control and Prevention. Updated November 10, 2022. Accessed November 13, 2022. https://covid.cdc.gov/covid-data-tracker/#datatracker-home
 
6. Zhang Z, He Q, Zhao W, et al. A heterologous V-01 or variant-matched bivalent V-01D-351 booster following primary series of inactivated vaccine enhances the neutralizing capacity against SARS-CoV-2 Delta and Omicron strains. J Clin Med. 2022;11(14):4164. doi:10.3390/jcm11144164
 
7. Stay up to date with COVID-19 vaccines including boosters. Centers for Disease Control and Prevention. Updated November 1, 2022. Accessed November 13, 2022. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html
 
8. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Centers for Disease Control and Prevention. Updated October 19, 2022. Accessed November 14, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#infection

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