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Natural, Vaccine-Induced, and Hybrid Immunity to COVID-19

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Seroprevalence surveys suggest that from the beginning of the pandemic to 2022, more than a third of the global population had been infected with SARS-CoV-2. As large numbers of people continue to be infected, the efficacy and duration of natural immunity, in terms of protection against SARS-CoV-2 reinfections and severe disease, are of crucial significance. The virus’s epidemiologic trajectory will be influenced by the trends in vaccine-induced and hybrid immunity.

Omicron’s Immune Evasion

Cases of SARS-CoV-2 reinfection are increasing around the world. According to data from the UK Health Security Agency, 650,000 people in England have been infected twice, and most of them were reinfected in the past 2 months. Before mid-November 2021, reinfections accounted for about 1% of reported cases, but the rate has now increased to around 10%. The reinfection risk was 16 times higher between mid-December last year and early January this year. Experts believe that this spike in reinfections is related to the spread of Omicron, which overtook Delta as the dominant variant. Nonetheless, other aspects should also be considered.

Omicron’s greater propensity to spread is not unrelated to its ability to evade the body’s immune defenses. This aspect was raised in a letter recently published in The New England Journal of Medicine. The authors reported that the effectiveness of previous infection in preventing reinfection against the Alpha, Beta, and Delta variants was around 90%, but it was only 56% against Omicron.

Natural Immunity

Natural immunity showed roughly similar effectiveness regarding protection against reinfection across different SARS-CoV-2 variants, with the exception of the Omicron variant. The risk of hospitalization and death was also reduced in SARS-CoV-2 reinfections vs primary infections. Observational studies indicate that natural immunity may offer equal or greater protection against SARS-CoV-2 infections compared with immunization with two doses of an mRNA vaccine, but the data are not fully consistent.

Natural immunity seems to be relatively long-lasting. Data from Denmark and Austria show no evidence that protection against reinfections wanes after 6 months. Some investigations indicate that protection against reinfection is lowest 4 to 5 months after initial infection and increases thereafter, a finding that might hypothetically be explained by persistent viral shedding, ie, misclassification of prolonged SARS-CoV-2 infections as reinfections. While no comparison was made against information pertaining to unvaccinated-not-previously-infected individuals, preliminary data from Israel suggest that protection from reinfection can decrease from 6 to more than 12 months after the first SARS-CoV-2 infection. Taken together, epidemiologic studies indicate that protection against reinfections by natural immunity lasts over 1 year with only moderate, if any, decline over this period. Among older individuals, immunocompromised patients, and those with certain comorbidities or exposure risk (eg, healthcare workers), rates of reinfection may be higher. It is plausible that reinfection risk may be a function of exposure risk.

There is accumulating evidence that reinfections may be significantly less severe than primary infections with SARS-CoV-2. Reduced clinical severity of SARS-CoV-2 reinfections naturally also makes sense from a biologic point of view, inasmuch as a previously primed immune system should be better prepared for a rechallenge with this virus.

Vaccine-Induced Immunity

The short-term (<4 months) efficacy of mRNA vaccines against SARS-CoV-2 is high and varies from 94.1% (Moderna) to 95% (BioNTech/Pfizer). This has been confirmed by randomized controlled trials and was subsequently confirmed in effectiveness studies in real-world settings. Waning efficacy was observed with respect to protection against SARS-CoV-2 infections (eg, only approximately 20% after about half a year in Qatar), whereas protection against severe disease was either sustained or showed only a moderate decline.

In individuals who received two doses of the BioNTech/Pfizer vaccine at least 5 months earlier, an additional vaccine dose, a so-called booster, significantly lowered mortality and severe illness. These findings suggest that the booster restored and probably exceeded the initial short-term efficacy of the initial vaccination.

Data are still emerging regarding the efficacy of boosters against the Omicron variants. Preliminary data suggest a far lower ability to restore protection from infection and vaccination. However, fatalities and hospitalizations remain low.

Natural Immunity vs Vaccine-Induced Immunity

Comparisons of natural immunity with vaccine-induced immunity are complicated by a series of biases and by combinations of biases — for example, the biases of comparisons between infected and uninfected, plus the biases of comparisons between vaccinated and nonvaccinated, with strong potential selection biases and confounding. Of particular note, the proportion of people previously infected and/or vaccinated may influence estimates of effectiveness. Regarding this point, one study compared unvaccinated patients with a prior SARS-CoV-2 infection and vaccinated individuals followed up from a week after the second vaccine dose onward vs a group of unvaccinated and not-previously-infected individuals. The findings showed that, compared to unvaccinated and not-previously-infected individuals, the natural immunity group and the vaccinated group had similar protection of 94.8% and 92.8% against infection, of 94.1% and 94.2% against hospitalization, and of 96.4% and 94.4% against severe illness, respectively.

Hybrid Immunity

The combination of a previous SARS-CoV-2 infection and a respective vaccination is called hybrid immunity. This combination seems to confer the greatest protection against SARS-CoV-2 infections, but several knowledge gaps remain regarding this issue.

Data from Israel showed that when the time since the last immunity-conferring event (either primary infection or vaccination) was the same, the rates of SARS-CoV-2 infections were similar in the following groups: individuals who had a previous infection and no vaccination, individuals who had an infection and were then vaccinated with a single dose after at least 3 months, and individuals who were vaccinated (two doses) and then infected. Severe disease was relatively rare overall.

Data on the efficacy of hybrid immunity point in the direction of hybrid immunity being superior, as compared to either vaccine-induced (without a booster) immunity or natural immunity alone. Timing and mode of vaccination of previously infected individuals to achieve optimal hybrid immunity are central questions that remain to be addressed in future studies.

Given that vaccination rates are continuously increasing and that by the beginning of 2022, perhaps half or more of the global population had already been infected with SARS-CoV-2, with the vast majority of this group not being officially detected, it would appear logical that future infection waves, even with highly transmissible variants of SARS-CoV-2, may be limited with respect to their maximum potential health burden. The advent of Omicron suggests that massive surges can occur even in populations with extremely high rates of previous vaccination and variable rates of prior infections. However, even then, the accompanying burden of hospitalizations and deaths is far less than what was seen in 2020 and 2021. One may argue that the pandemic has already transitioned to the endemic phase and that Omicron is an endemic wave occurring in the setting of already widespread population immunity.

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