Should prior COVID-19 infection count when it comes to vaccine mandates? That is the question that many scientists and medical researchers are struggling to answer. As daily COVID-19 cases continue to increase worldwide, natural immunity and questions around the immune response in those infected with COVID-19 remain uncertain. TrialSite has previously reported on the Israeli study that found natural immunity exceeds vaccine-induced immunity, and that American health agencies should factor in natural immunity for precision vaccination. New studies are now looking into where immune cells following infection with SARS-CoV-2 are stored in the body, and how effective natural immunity is in preventing re-infection. 

On May 10, 2021, the World Health Organization (WHO) published a Scientific Brief titled “Covid-19 Natural Immunity”. The objective of the brief was to replace the WHO April 2020 document titled “Immunity passports in the context of COVID-19”, and to summarize what was understood about natural immunity at the time of publication, by conducting a literature review of scientific publications. 

The brief acknowledges that the strength and duration of natural immune responses are not yet completely understood, and vary by age and severity of infection. By studying published literature, WHO concluded that most people that were infected by SARS-CoV-2 remained protected against reinfection for approximately 6 to 8 months after infection. 

On October 29, 2021, the Centers for Disease Control (CDC) published a brief providing an overview of scientific evidence around infection-induced and vaccine-induced immunity. In this brief, the CDC states that “fully vaccinated individuals and those previously infected with SARS-CoV-2 each have a low risk of subsequent infection for at least 6 months.” Subscribe to the Trialsitenews “SARS-CoV-2” ChannelNo spam – we promise

Despite these findings, the CDC still recommends COVID-19 vaccinations for all eligible persons, including those previously infected with SARS-CoV-2. 

Measuring Immune Responses

Immune responses after infection with a virus are measured by detecting virus-specific antibodies (like IgA, IgM, IgG) or total antibodies using immunoassays, or by detecting memory B cells and CD4+ and CD8+ T cells. 

Dan, Mateus, and Crotty (2021) published a paper in Science that investigated the natural immune response to SARS-CoV-2 up to 8 months after infection with the virus. The authors looked at 188 human infection cases with differing severities (mild, moderate, and severe), and described the dynamics of the SARS-CoV-2 memory B cells, CD8+ T cells, and CD4+ T cells for more than 6 months after the initial infection. The authors found that “substantial immune memory is generated after COVID-19, involving all four major types of immune memory.” 95% of the cases showed retention of immune memory at approximately 6 months after infection. These results are likely to have implications for how the pandemic is managed. 

Another study by Wajnberg, Amanat, and Cordon-Cardo (2020) published in Science investigated antibodies produced after infection with SARS-CoV-2. The authors looked at more than 30,000 infected individuals to assess the robustness of the antibody response. They discovered that antibody titers against spike proteins of SARS-CoV-2 lasted for at least 5 months after infection. These results suggest that the chance of reinfection by the virus is lower than it was feared at the time. 

A third study by Turner et al. (2021) and published in Nature looked at the impact COVID-19 has on bone marrow plasma cells in humans. Bone marrow plasma cells are an essential source of antibodies. By studying cases of individuals who had a mild SARS-CoV-2 infection, the authors found that a mild infection resulted in a robust, antigen-specific immune memory in humans. 

Natural Immunity vs Vaccine-Induced Immunity

In 2015, the Michigan state government published a document titled “Comparing Natural and Vaccine Immunity”. The document cited several CDC links, and one of the key points of the document is: “It is true that natural infection almost always causes better immunity than vaccines.” The question then to ask is: how does natural immunity compare to vaccine-induced immunity in COVID-19?

Research by Gazit et al. (2021), currently available in preprint, set out to compare SARS-CoV-2 natural immunity to vaccine-induced immunity by looking at reinfections and breakthrough infections. The study looked at three groups: 1) uninfected individuals who received a two-dose regimen of the Pfizer vaccine, 2) previously infected individuals who were not vaccinated, and 3) previously infected and single-dose vaccinated individuals. The paper found that “natural immunity confers longer-lasting and stronger protection against symptomatic disease and hospitalization caused by the Delta variant, compared to the two-dose vaccine-induced immunity.” 

Contradicting this, the CDC issued a study that looked at confirmed COVID-19 cases among hospitalized adults, those that either had infection-induced or mRNA vaccine-induced immunity, using data from the Vision Network (which is funded by the CDC). SARS-CoV-2 was confirmed in 5.1% of fully vaccinated persons and 8.7% of unvaccinated, previously infected persons. The study concludes, “All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.”

Impacts of Variants on Immunity

Throughout the pandemic, several Variants of Concern have emerged with mutations on the spike protein of the virus. These variants may result in decreased natural- and vaccine-induced immunity from antibodies produced. 

A paper by Haveri et al. (2021) published in the European Journal of Immunology looked at the persistence of neutralizing antibodies a year after SARS-CoV-2 infection. The authors looked at 376 unvaccinated individuals that were infected, and after 12 months, 98% had detectible IgG virus-specific antibodies, and 91% had neutralizing antibodies against the wild-type virus (the original Wuhan virus). Among a subset of 78 persons assessed for antibodies against specific variants, neutralizing antibodies were detected in 84%, 68%, and 55% for Alpha, Delta, and Beta variants respectively. 

The latest Omicron variant may, however, pose a threat to natural immunity. A paper that is currently in preprint by Pulliam et al. (2021) from South Africa identified an increased risk of SARS-CoV-2 reinfection with the emergence of Omicron in South Africa. The author looked at 2,796,982 individuals who had a positive test result 90 days before November 27, 2021. In that group, 35,670 reinfections were suspected. These findings will have implications for public health planning and pose the question of whether Omicron is able to escape vaccine-induced immunity as well. 

Emerging Data on Natural Immunity

As the pandemic continues, more studies will arise on the robustness of natural immunity against COVID-19 reinfection, and comparisons between natural immunity and vaccine-induced immunity. Infections by previous coronaviruses – most notably SARS and MERS – have resulted in T cell immunity that has exceeded 15 years. Could we expect the same from COVID-19 infection?

With escalating reports of adverse events following COVID vaccination, the potential role of natural immunity is increasingly significant. On the other hand Omicron may pose a new challenge. TrialSite will continue to report on the evolving scientific evidence regarding natural immunity following SARS-CoV-2 infection.

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