The Staggering Success of Vaccines

COVID-19 Protection From Hybrid Immunity Stronger Than Recent Vaccination Alone

Protection against symptomatic COVID-19 infection among adults in the United States is strong for those with hybrid immunity from prior infection and recent vaccination but moderate for those with recent vaccination alone, according to study results published in The Journal of Infectious Diseases.

Researchers in the US conducted an analysis of prospective cohort studies from September 2022 to July 2023 to evaluate the vaccine effectiveness (VE) of monovalent and bivalent COVID-19 vaccines against symptomatic infection among adults with and without a history of SARS-CoV-2. The analysis included adults residing in Washington, Oregon, Michigan, and Tennessee. Cox proportional hazard models were used to estimate infection risk, with adjustment for covariates. Prior COVID-19 infection and recency of vaccination were considered in calculations of VE. 

A total of 3344 adults were included in the final analysis, of whom the median age was 41 (IQR, 36-46) years, 67.2% were women, 69.3% were White, 60.8% had at least 1 chronic health condition, and 43.5% reported at least 1 prior COVID-19 infection. Nearly half (49.7%) of the population reported receipt of at least 1 bivalent COVID-19 vaccine dose, with lower uptake observed in those with vs without prior infection (46.3% vs 54.5%).

During the study period, 751 (22.5%) patients tested positive for laboratory-confirmed SARS-CoV-2, of whom 58.6% reported symptomatic disease. Overall, the rate of SARS-CoV-2 positivity in the follow-up period was lower among patients with vs without a history of infection (17.2% vs 26.5%).

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These findings suggest that hybrid immunity provided the strongest protection against SARS-CoV-2 infection, with the bivalent vaccine alone providing some protection against SARS-CoV-2 infection…

Compared with unvaccinated patients and those who reported receipt of an original monovalent vaccine dose, the adjusted VE of the bivalent vaccine against laboratory-confirmed infection was 37.2% (95% CI, 12.3-55.7) within 7 to 59 days after receipt of vaccination and 21.1% (95% CI, -0.5-37.1) within 60 to 179 days after receipt. For patients with hybrid immunity from prior infection, the adjusted VE of the bivalent vaccine was 62.2% (95% CI, 46-74.5) within 7 to 179 days after receipt and 39.4% (95% CI, 12.5-61.6) at 180 days or more after receipt.

Further comparisons against the same reference group showed that, when combined with prior infection, the adjusted VE of the bivalent vaccine against symptomatic disease was 73% (95% CI, 57-84.2) within 7 to 179 days after receipt and 56.7% (95% CI, 31.1-78.4%) at 180 days or more after receipt. The adjusted VE of the monovalent vaccine combined with prior immunity was 59.5% (95% CI, 32.3-79) against laboratory-confirmed infection and 80.6% (95% CI, 57.3-94.4) against symptomatic disease.

Study limitations include variations in SARS-CoV-2 testing methods and illness definitions across study sites, potential social desirability and recall bias, and the possibility of undetected infections due to antibody waning. 

According to the researchers, "These findings suggest that hybrid immunity provided the strongest protection against SARS-CoV-2 infection, with the bivalent vaccine alone providing some protection against SARS-CoV-2 infection…" However, "[V]accine effectiveness waned more rapidly than hybrid immunity and after 6 months there was no measurable protection," they added.

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

This article originally appeared on Infectious Disease Advisor

Hybrid Immunity: Science Unveiled The Importance Of Recoverees Getting Vaccinated Against COVID-19

People who had been infected with the coronavirus and accessed doses of COVID-19 vaccines have "hybrid immunity". There are already 4 scientific studies that provide evidence that these vaccines provide important additional protection to these people.

Vaccines have already been shown to be very effective in protecting people who have never had COVID-19, but their effectiveness in preventing symptoms and severe outcomes in people who have already had been infected was, until recently, less clear.

After two years of a pandemic in which nearly 500 million people have been infected and 59% of humanity have been vaccinated with the primary scheme - according to information from OurWorldIndata -, studies have highlighted the importance of being vaccinated for those who have natural immunity after recovering from the disease.

One of the two studies published in the medical journal The Lancet Infectious Diseases analyzed the health data of more than 200,000 people, between 2020 and 2021, when Brazil was most affected by the coronavirus , being the second country in the world with the highest number of deaths from COVID.

Researchers from Brazil found that in people who have already had COVID-19, the Pfizer and AstraZeneca vaccines were 90 percent effective against hospitalization and death, China's CoronaVac vaccine was 81 percent, and Johnson & Johnson's single-dose inoculant was 58 percent.

"All four vaccines have been shown to provide significant additional protection to those with previous COVID-19 infection," said study author Julio Croda, of the Federal University of Mato Grosso do Sul.

"Hybrid immunity due to exposure to natural infection and vaccination is likely to be the norm worldwide and could provide long-term protection even against emerging variants," said Pramod Kumar Garg, of the Indian Institute of Translational Health Science and Technology, in a related commentary to the studio.

Meanwhile, another study that used Sweden's national registry until October 2021 found that people who recovered from COVID retained a high level of protection against re-infection up to 20 months. And it also found that people with hybrid immunity from two doses of vaccines had a 66% lower risk of re-infection than those with only natural immunity.

Paul Hunter, professor of medicine at the University of East Anglia who did not participate in the study, told AFP that the 20 months of "very good protection" of natural immunity was "much better than would be expected for the original two-dose vaccine schedule." But he warned that both studies were conducted before the Ómicron variant became dominant worldwide, and that it had "markedly decreased the protective value of a previous infection."

A study conducted in Qatar and published on the MedRXIV pre-publication website last week revealed the protection offered by hybrid immunity against Ómicron. He found that three doses of the vaccine were 52% effective against symptomatic infection of the BA.2 Omicron subvariant, but that figure skyrocketed to 77% when the patient had been previously infected.

The study, which has not been peer-reviewed, concluded that "hybrid immunity resulting from previous infection and recent booster vaccination confers the greatest protection" against subvariants BA.1 and BA.2.

Also in the United States, Marion Pepper, associate professor in the Department of Immunology at the University of Washington School of Medicine, published other research in the journal Cell and explained why "hybrid immunity" gives better protection. They compared differences in the immune response to coronavirus across three doses of the vaccine in 30 people who had been previously infected and in 24 who had been vaccinated but never infected.

They found that, after vaccination, those who had been previously infected generated more memory B cells, which generate antibodies that can neutralize the virus and prevent infection. These memory B cells in people with hybrid immunity also generated a greater variety of antibodies that can not only neutralize the original strain of the virus, but also newer variants such as Delta and Omicron.

"Even if their first infection was caused by the oldest strain, the Wuhan strain, and the vaccine they received was based on that strain, people with hybrid immunity were able to generate neutralizing antibodies against each variant," Pepper said.

Hybrid immunity also generated a more specific cellular immune response to combat viral infections, called the Th1 response. In this response, immune cells called CD4+ T cells release inflammatory signals, namely a cytokine called interferon-gamma that is antiviral. CD4+ T cells from previously infected individuals were also found to produce more Interleukin-10, which can suppress inflammation and potentially prevent pathology.

"While additional vaccination was able to increase the number of CD4+ T cells in which they had not been infected to levels that had been infected, it could not generate the same quality of CD4+ T cell response seen in those with hybrid immunity," Pepper said.

Several factors could explain why hybrid immunity seems more robust. One factor could simply be time. Upon exposure to a pathogen, immune cells in the lymph nodes refine the immune response. This process of immune maturation generates more effective antibodies and cells against the new infection.

In the case of the hybrid immunity group, a year passed from the moment of infection until they received the vaccine. In contrast, individuals in the vaccine-only group received their second dose only a few weeks after the first dose, which gave the immune system much less time to refine its response.

Another factor may be where the immune system first interacts with an invading pathogen. Different parts of the body have different environments that determine how the immune system responds to infection. The immune cells of the study participants with hybrid immunity were first found with the virus in their lungs and nasal passages. In contrast, cells from the vaccine-only group were first found with the viral protein in the muscle where they received the vaccine.

Exposure to the lungs and mucosal tissues, such as those found in the nasal passages, is likely to generate a better immune response to a respiratory pathogen because cells may be better retained in these locations, Pepper said. His group's findings could help scientists design vaccines that take advantage of this effect, such as those that can be administered into the nasal passages or inhaled directly into the lung.

Although vaccination after a previous infection appears to produce a greater immune response to SARS-CoV-2 infection, it is essential that people who have been infected get vaccinated to get this benefit, Dr. Pepper advised. "People who have had COVID-19 should definitely get vaccinated. Not only does immunity to infection decrease over time, but vaccination is also necessary to create this hybrid immunity," he added. His research was supported by the National Institutes of Health, the Burroughs Wellcome Fund and Emergent Ventures.

While "hybrid immunity" provides better protection, the chief scientist of the World Health Organization (WHO), Dr. Soumya Swamin, warned that caution should be maintained. "Hybrid immunity doesn't mean people should let their guard down with the mask, distancing and hand hygiene," he said. His recommendation is because it is not known how long the natural immunity from infection can last in each person and in addition vaccines do not prevent 100% of infections. "In addition, a person can have the coronavirus even if they are vaccinated," he said.

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Superimmunity Against COVID: How Is It Generated, According To Harvard Experts

More and more scientific evidence postulates that vaccination plus natural immunity from exposure to coronavirus leads to particularly strong protection, even against many variants of the virus. The so-called hybrid immunity, that is, the natural immunity of an infection combined with the immunity provided by the vaccine, seems to result in stronger protection than simple infection or separate vaccination.

Thus, the vaccine against COVID-19 plus infection can lead to months of immunity, according to Harvard scientists in new studies carried out to find out what protection this acquired dual immunity confers.

Miguel Hernan, an epidemiologist at Harvard's T.H. Chan School of Public Health in Boston, Massachusetts, said that studies show the near-universal benefit of full vaccination, even in those who have already suffered COVID-19. And he warned that some nations have issued statements encouraging people who have had COVID-19 to receive a single dose of vaccine: a measure that "may be justified in an environment of shortage of vaccines, but that is not appropriate when it comes to being properly protected at the immune level," said the expert.

Not long after countries began implementing vaccines, researchers began to notice unique properties of vaccine responses from people who had previously been infected and recovered from COVID-19.

"We saw that antibodies reach these astronomical levels that exceed what is obtained with two doses of vaccine alone," explained Rishi Goel, an immunologist at the University of Pennsylvania in Philadelphia, who is part of a team that studies superimmunity, or hybrid immunity, as most people call it scientists.

In a recent scientific study carried out in Brazil and published in The Lancet, he collected data from patients infected and vaccinated before the emergence of the Ómicron variant. Julio Croda, infectiologist and epidemiologist at the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Croda and his colleagues analyzed Brazil's vaccination and infection databases to prove that the claims of Brazilian President Jair Bolsonaro, who said that since he already had COVID-19, so it was not necessary to get vaccinated, were wrong.

Researchers found that between February 2020 and November 2021, people who had previously been infected with SARS-CoV-2 and then received a dose of the vaccine — manufactured by Pfizer-BioNTech, Oxford-AstraZeneca, SINovac, or Johnson & Johnson — avoidedup to 45% of COVID-19 cases that the group would have been expected to contract without vaccination.

Full courses of two-dose vaccines prevented up to 65% of expected infections and more than 80% of expected cases of severe COVID-19. "The big message is this: it is necessary to have a complete vaccination schedule for COVID-19," Croda said.

Some authorities consider previous infections when deciding who should have access to public places, such as concerts and restaurants, but others consider only vaccination status. Peter Nordström, an epidemiologist at the University of Umeå, in Sweden, says that this dichotomy led him and his colleagues to do another study.

Using records collected by the Swedish Public Health Agency between March 2020 and October 2021, the researchers showed that Swedish residents who had been infected with SARS-CoV-2 had a 95% reduction in the risk of contracting COVID-19 compared to people who had not had immunity, and protection grew during the three months after infection and lasted until at least 20 months after infection. One dose of the vaccine reduced the risk of infection by about 50% more, and a second dose stabilized additional protection for six months after vaccination.

Although vaccination increases protection, Nordström believes that the immunity offered by infection alone is worthy of consideration. "Maybe we should have immunity passports instead of vaccination passports. Therefore, it is considered immune, and it is less likely to transmit the disease, if you have been fully vaccinated or if you have had a previous documented infection," he said.

Epidemiologist Victoria Hall of the UK Health Safety Agency in London and her colleagues conducted the third study by monitoring infections in thousands of healthcare workers from March 2020 to September 2021. Researchers found that previous infections prevented more than 80% of COVID-19 cases that would otherwise have been expected in the year after infection, but protection dropped to around 70% after a year.

Study participants who received two doses of the Pfizer-BioNTech or Oxford-AstraZeneca vaccine after infection had close to 100% protection for at least six to eight months after the second dose. "Protection declined over time after vaccination and also after infection, but remained persistently high in those with hybrid immunity," Hall concluded of recent research.

More research on hybrid immunity

Initial studies of people with hybrid immunity found that their serum, the portion of blood that contains antibodies, was much better able to neutralize immune-evading strains, such as the Beta variant identified in South Africa, and other coronaviruses, in compared to vaccinated people who had never faced SARS-CoV-2. It was not clear whether this was due only to high levels of neutralizing antibodies or other properties.

The most recent studies suggest that hybrid immunity is due, at least in part, to immune agents called memory B cells. Most of the antibodies produced after infection or vaccination come from short-lived cells called plasmablasts, and antibody levels drop when these cells inevitably die. Once plasmablasts disappear, the main source of antibodies becomes much rarer memory B cells that are triggered by infection or vaccination.

A separate study found that, compared to mRNA vaccination, infection leads to a group of antibodies that recognize variants more uniformly by targeting various peak regions. The researchers also found that people with hybrid immunity produced consistently higher levels of antibodies, compared to vaccinated people who were never infected, for up to seven months. Antibody levels were also more stable in people with hybrid immunity, reports the team led by immunologist Duane Wesemann at Harvard Medical School in Boston, Massachusetts.

Many hybrid immunity studies have not followed vaccine recipients who had not been previously infected for as long as those who recovered from COVID-19, and their B cells may produce antibodies that gain potency and amplitude over time, additional doses of vaccine, or both. It can take months for a stable group of memory B cells to establish and mature.

"It's not surprising that people who are infected and vaccinated are getting a good response," said Ali Ellebedy, B-cell immunologist at the University of Washington in St. Louis, Missouri. "We're comparing someone who started the race three or four months ago to someone who started the race now."

There is some evidence that people who received both jabs without being previously infected appear to be catching up. Ellebedy's team collected lymph node samples from individuals vaccinated with mRNA and found signs that some of their vaccine-triggered memory B cells were acquiring mutations, up to 12 weeks after the second dose, which allowed them to recognize various coronaviruses, including some that cause common colds.

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