Covidiot News - How Regular Vaccine Boosters Are Giving Even More Protection.

Health-care workers received the first doses of the COVID-19 vaccine in December 2020. Repeat booster vaccination with updated versions of the vaccine promotes antibodies against a wide range of variants, as well as related coronaviruses.

Repeat COVID-19 vaccinations elicit antibodies that neutralize variants, other viruses – Washington University School of Medicine in St. Louis

A new study has shown that regular boosters of the COVID-19 vaccines against each new variant, give protection against a broad range of variants probably including variants yet to emerge, as well as related viruses.

This was the conclusion of a study by researchers at Washington University School of Medicine in St. Louis. The concern had been that, like the flu vaccines, earlier vaccinations tend to inhibit the formation of newer antibodies, but the study showed that not only are antibodies raised to the new variant but repeated vaccinations 'train' the immune system to produce a broad spectrum of antibodies.

This very welcome news to someone who has just had his 7th booster but still contracted a mild infection at the end of last summer on a trip to France, especially as we're going to Czechia in a few days’ time.

The research findings are the subject of a pre-edited paper in nature which is sadly behind a paywall, so we only have the Abstract. However, the researchers have provided more detail in a Washington University news release:

The COVID-19 pandemic is over, but the virus that caused it is still here, sending thousands of people to the hospital each week and spinning off new variants with depressing regularity. The virus’s exceptional ability to change and evade immune defenses has led the World Health Organization (WHO) to recommend annual updates to COVID-19 vaccines.

But some scientists worry that the remarkable success of the first COVID-19 vaccines may work against updated versions, undermining the utility of an annual vaccination program. A similar problem plagues the annual flu vaccine campaign; immunity elicited by one year’s flu shots can interfere with immune responses in subsequent years, reducing the vaccines’ effectiveness.

A new study by researchers at Washington University School of Medicine in St. Louis helps to address this question. Unlike immunity to influenza virus, prior immunity to SARS-CoV-2, the virus that causes COVID-19, doesn’t inhibit later vaccine responses. Rather, it promotes the development of broadly inhibitory antibodies, the researchers report.

The study, available online in Nature, shows that people who were repeatedly vaccinated for COVID-19 — initially receiving shots aimed at the original variant, followed by boosters and updated vaccines targeting variants — generated antibodies capable of neutralizing a wide range of SARS-CoV-2 variants and even some distantly related coronaviruses. The findings suggest that periodic re-vaccination for COVID-19, far from hindering the body’s ability to recognize and respond to new variants, may instead cause people to gradually build up a stock of broadly neutralizing antibodies that protect them from emerging SARS-CoV-2 variants and some other coronavirus species as well, even ones that have not yet emerged to infect humans.

The first vaccine an individual receives induces a strong primary immune response that shapes responses to subsequent infection and vaccination, an effect known as imprinting. In principle, imprinting can be positive, negative or neutral. In this case, we see strong imprinting that is positive, because it’s coupled to the development of cross-reactive neutralizing antibodies with remarkable breadth of activity.

Professor Michael S. Diamond, MD, PhD, corresponding author
Herbert S. Gasser Professor of Medicine.
And professor of molecular microbiology and of pathology & immunology.
Department of Pathology & Immunology
Washington University School of Medicine, St. Louis, MO, USA.

Imprinting is the natural result of how immunological memory works. A first vaccination triggers the development of memory immune cells. When people receive a second vaccination quite similar to the first, it reactivates memory cells elicited by the first vaccine. These memory cells dominate and shape the immune response to the subsequent vaccine.

In the case of the flu vaccine, imprinting has negative effects. Antibody-producing memory cells crowd out new antibody-producing cells, and people develop relatively few neutralizing antibodies against the strains in the newer vaccine. But in other cases, imprinting can be positive, by promoting the development of cross-reactive antibodies that neutralize strains in both the initial and subsequent vaccines.

To understand how imprinting influences the immune response to repeat COVID-19 vaccination, Diamond and colleagues including first author Chieh-Yu Liang, a graduate student, studied the antibodies from mice or people who had received a sequence of COVID-19 vaccines and boosters targeting first the original and then omicron variants. Some of the human participants also had been naturally infected with the virus that causes COVID-19.

The first question was the strength of the imprinting effect. The researchers measured how many of the participants’ neutralizing antibodies were specific for the original variant, the omicron variant or both. They found that very few people had developed any antibodies unique to omicron, a pattern indicative of strong imprinting by the initial vaccination. But they also found few antibodies unique to the original variant. The vast majority of neutralizing antibodies cross-reacted with both.

The next question was how far the cross-reactive effect extended. Cross-reactive antibodies, by definition, recognize a feature shared by two or more variants. Some features are shared only by similar variants, others by all SARS-CoV-2 variants or even all coronaviruses. To assess the breadth of the neutralizing antibodies, the researchers tested them against a panel of coronaviruses, including SARS-CoV-2 viruses from two omicron lineages; a coronavirus from pangolins; the SARS-1 virus that caused the 2002-03 SARS epidemic; and the Middle Eastern Respiratory Syndrome (MERS) virus. The antibodies neutralized all the viruses except MERS virus, which comes from a different branch of the coronavirus family tree than the others.

Further experiments revealed that this remarkable breadth was due to the combination of original and variant vaccines. People who received only the vaccines targeting the original SARS-CoV-2 variant developed some cross-reactive antibodies that neutralized the pangolin coronavirus and SARS-1 virus, but the levels were low. After boosting with an omicron vaccine, though, the cross-reactive neutralizing antibodies against the two coronavirus species increased.

Taken together, the findings suggest that regular re-vaccination with updated COVID-19 vaccines against variants might give people the tools to fight off not only the SARS-CoV-2 variants represented in the vaccines, but also other SARS-CoV-2 variants and related coronaviruses, possibly including ones that have not yet emerged.

At the start of the COVID-19 pandemic, the world population was immunologically naïve, which is part of the reason the virus was able to spread so fast and do so much damage. We do not know for certain whether getting an updated COVID-19 vaccine every year would protect people against emerging coronaviruses, but it’s plausible. These data suggest that if these cross-reactive antibodies do not rapidly wane — we would need to follow their levels over time to know for certain — they may confer some or even substantial protection against a pandemic caused by a related coronavirus.

Professor Michael S. Diamond, MD, PhD.

Incidentally, why these boosters are needed and why this study is such good news can be seen from the following chart of the changing proportions of SARS-CoV-2 variants in the UK over time. This is a lovely example of how a mutation can give rise to a variant which out-competes other variant and come to dominate the species gene pool.

SARS-CoV-2 genomic lineages
Weekly percentage of sequenced cases attributed to each lineage group.
Data is shown by week of specimen collection. Up to and including 1 April 2024

In their paper the scientists refer to 'sarbecoviruses', which is a new term to me, so first a little AI background:

What are sarsbecoviruses? Sarbecoviruses are a subgroup of coronaviruses within the genus Betacoronavirus. They are known for infecting bats and other mammals, and they have significant relevance to human health due to their role in zoonotic disease transmission. The term "sarbecovirus" is derived from "SARS-related Betacoronavirus," reflecting their close relationship to the Severe Acute Respiratory Syndrome (SARS) coronaviruses.

Key Characteristics of Sarbecoviruses:

1. Genomic Structure: Sarbecoviruses have a single-stranded positive-sense RNA genome, typical of coronaviruses, with characteristic structural proteins including the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.
2. Spike Protein: The spike protein is crucial for viral entry into host cells. It binds to host receptors, facilitating cell membrane fusion and viral entry. For SARS-CoV-1 and SARS-CoV-2, the receptor is angiotensin-converting enzyme 2 (ACE2).
3. Host Range and Reservoirs: Bats are considered the primary natural reservoirs for sarbecoviruses. However, these viruses can spill over into other species, including humans, often through intermediary hosts like civet cats (in the case of SARS-CoV-1) or potentially pangolins (suggested in the case of SARS-CoV-2).
4. Zoonotic Potential: Sarbecoviruses have a high zoonotic potential, meaning they can jump from animals to humans. This is exemplified by the SARS-CoV-1 outbreak in 2002-2003 and the ongoing SARS-CoV-2 (COVID-19) pandemic, which started in late 2019.
5. Recombination and Mutation: These viruses are prone to genetic recombination and mutations, which contribute to their ability to adapt to new hosts and environments, potentially leading to new outbreaks.

Significant Sarbecoviruses:

1. SARS-CoV-1: Responsible for the SARS outbreak in 2002-2003, which resulted in significant morbidity and mortality before being contained.
2. SARS-CoV-2: The causative agent of COVID-19, identified in December 2019. It has caused a global pandemic with widespread health, social, and economic impacts.

Research and Public Health:

Due to their potential to cause severe respiratory illnesses and pandemics, sarbecoviruses are a major focus of virological and epidemiological research. Efforts are ongoing to understand their ecology, genetic diversity, mechanisms of transmission, and to develop effective vaccines and antiviral treatments.

Understanding sarbecoviruses is crucial for predicting and preventing future outbreaks, given their demonstrated capacity to cause widespread disease in humans.

Abstract
Immune imprinting is a phenomenon in which prior antigenic experiences influence responses to subsequent infection or vaccination^1,2. The effects of immune imprinting on serum antibody responses after boosting with variant-matched SARS-CoV-2 vaccines remain uncertain. Here, we characterized the serum antibody responses after mRNA vaccine boosting of mice and human clinical trial participants. In mice, a single dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling generation of type-specific antibodies. However, imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron vaccine. In both SARS-CoV-2 infected or uninfected humans who received two Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with Omicron variants as well as more distantly related sarbecoviruses. Because serum neutralizing responses against Omicron strains and other sarbecoviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series. Thus, the antibody response to Omicron-based boosters in humans is imprinted by immunizations with historical mRNA-1273 vaccines, but this outcome may be beneficial as it drives expansion of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and distantly related sarbecoviruses.

Liang, CY., Raju, S., Liu, Z. et al.
Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines.
Nature (2024). https://doi.org/10.1038/s41586-024-07539-1

© 2024 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

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