Vaccine-induced immunity is one of the most important methods to control disease spread and prevent the resurgence of infection. What remains unclear is why some vaccines offer longer protection while others don't. A recent study sought to find this answer for the COVID mRNA-based vaccines. The results seem very promising.

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Vaccines may induce strong, persistent immunity to COVID-19

We have some good news from the vaccine front. Advances in vaccine research to vanquish the COVID-19 virus are presently leading to impressive beneficial results every week if not every day. Researchers introduced the concept of using mRNAs as vaccines over 30 years ago. They made key refinements and improved the biological stability and translation capacity of exogenous mRNA. This, in turn, enabled the development of these molecules as vaccines. The arrival of SARS-CoV-2 in December 2019 and the pandemic that followed have offered an opportunity to test the potential of this vaccine platform.

Pfizer and Moderna vaccines were the first vaccines with mRNA technology to get Emergency Use Approval from the Food and Drug Administration. Most vaccines, which provide bits of viral or bacterial proteins to trigger an immune response, whereas, mRNA-based vaccines provide instructions for the body to build and release foreign proteins, such as the spike protein in the case of the SARS-CoV-2 virus. These vaccines performed well in clinical trials, and they have been widely credited with reducing disease. However, concerns over how long the immunity induced by the new vaccine technology will last, remained unclear.

On 28 June 2021, the researchers at Washington University School of Medicine in St. Louis published a paper in the journal Nature, which has found evidence that the immune response to such vaccines is both strong and potentially long-lasting. Nearly four months after the first dose, people who received the Pfizer vaccine still had so-called germinal centres in their lymph nodes churning out immune cells directed against SARS-CoV-2, the virus that causes COVID-19. Germinal centres, which form as the result of natural infection or vaccination, are boot camps for immune cells, a place where inexperienced cells are trained to better recognise the enemy and to get their weapons sharpened. A better germinal centre response may equal a better vaccine.

Since December 2020 when FDA granted Emergency Use Authorisation to Pfizer-BioNTech and Moderna COVID-19 vaccines, hundreds of millions of people have received one of the two SARS-CoV-2 mRNA-based vaccines. Both vaccines demonstrated notable immunogenicity in phase 1/2 studies and efficacy in phase 3 studies.

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Initial observations on protection

In April, both Pfizer and Moderna reported that their vaccines provided at least six months of protection. They based their reports on tracking whether the vaccinated people came down with COVID-19. Other groups have monitored antibody levels in the blood and concluded that the vaccine provides at least months of protection. But nobody had looked to see how the immune response was developing in the body, which could provide important clues to the strength and persistence of the immune response without requiring years of follow-up.

So far, the specialists knew that the period over which protection lasts vary from vaccine to vaccine. Scientists don't fully understand why vaccines, such as the one for smallpox, induce strong protection that lasts a lifetime, while others, such as the vaccine for whooping cough, need regular boosters. According to many specialists, the difference lies in the quality of the germinal centres induced by different vaccines.

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Do these vaccines induce robust and persistent germinal centre (GC) reactions that are critical for generating high-affinity and durable antibody responses?

Importance of germinal centres in lymph nodes

According to senior author Dr Ali Ellebedy, an associate professor of pathology & immunology, medicine and molecular microbiology, the germinal centres are the key to a persistent, protective immune response. "Germinal centres are where our immune memories are formed. And the longer we have a germinal centre, the stronger and more durable our immunity will be because there's a fierce selection process happening there, and only the best immune cells survive,” Dr Ellebedy clarified.

Assessing whether this new kind of vaccine induces a good germinal centre response was truly a multidisciplinary effort. A press release from the University disclosed:

"Ellebedy and co-first author Jackson Turner, PhD, an instructor in pathology & immunology, teamed up with co-senior author Rachel Presti, MD, PhD, an associate professor of medicine, and co-first author Jane O'Halloran, MD, PhD, an assistant professor of medicine, and started the study once the first COVID-19 vaccine became available in mid-December 2020. The team enlisted the help of co-authors Sharlene Teefey, MD, and William Middleton, MD, both professors of radiology, to perform ultrasound-guided sampling of the minuscule germinal centres in lymph nodes in the armpit."

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Sampling germinal centres in lymph nodes

Teefey and Middleton extracted cells from 14 people who received the Pfizer vaccine. They obtained the samples three weeks after the first dose (just prior to administration of the second dose), and at weeks four, five and seven. Ten of the participants gave additional samples 15 weeks after the first dose. None of the participants previously had been infected with the virus that causes COVID-19.

Three weeks after the first dose, all 14 participants had formed germinal centres with B cells producing antibodies that target a key SARS-CoV-2 protein. The response expanded greatly after the booster shot and then stayed high. Interestingly, even 15 weeks after the first dose, eight of 10 people still had detectable germinal centres containing B cells targeting the virus. "This is evidence of a really robust immune response." 

Dr Presti added, "Your immune system uses germinal centres to perfect the antibodies so they can bind well and last as long as possible. The antibodies in the blood are the end result of the process, but the germinal centre is where it is happening."

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Antibodies in blood samples

The researchers also obtained blood samples from 41 people who received the Pfizer vaccine, including eight who previously had been infected with the virus that causes COVID-19. They obtained the samples prior to the administration of each dose of the vaccine, as well as at weeks four, five, seven and 15 after the first dose. In people without prior exposure to the virus, antibody levels rose slowly after the first dose and peaked one week after the second. People who previously had been infected already had antibodies in their blood before the first dose. Their levels shot up quickly after the first dose and peaked higher than the uninfected participants' levels.

"We didn't set out to compare the effectiveness of vaccination in people with and without a history of infection, but when we looked at the data we could see an effect," Dr O'Halloran disclosed. "If you've already been infected and then you get vaccinated, you get a boost to your antibody levels. The vaccine clearly adds benefit, even in the context of prior infection, which is why we recommend that people who have had COVID-19, get the vaccine,” she added.

A major finding was that vaccination led to high levels of neutralising antibodies effective against three variants of the virus, including the beta variant from South Africa that showed some resistance to vaccines. Vaccination induced stronger antibody responses in people who had recovered from SARS-CoV-2 infection compared to those who had never been infected.

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Expert comments

In a press release from the Science Media Centre, London, Prof Danny Altmann, Professor of Immunology at Imperial College London, commented with calm contemplation:

“So much of COVID-19 immunology has had to be discovered at breakneck speed, that it has sometimes been necessary to stand back from the tsunami of immune measurements, take a deep breath, and remember our basic immunology. This is such a moment, in the form of a terribly elegant and impactful study. It involves looking at immunity to a spike in people given two Pfizer doses (with or without prior infection). Like many other studies, antibodies are measured, as are the ‘plasmablasts’ – B cells in the blood making the antibodies. Because there has been so much alarm over the suggestion that antibodies wane rapidly and immune memory may not be established, the team here added a really novel, additional experiment: they used a fine needle to sample some of the memory cells in the lymph node under the arm – the place where white blood cells actually get together after vaccination to build a robust, long-term immune response. For at least 3-months, these needle aspirates are found to contain memory cells that have undergone all the expected changes to lay down high-quality immune memory, such as changing antibody sequences to evolve ones of higher quality fit for the virus,” Professor Altmann concluded that this offers cause for optimism that, in most people, responses to vaccination will be long-lasting.

Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee stated that we are so lucky to have been able, so quickly, to develop several highly effective COVID-19 vaccines. “As time goes by, we are learning more and more about just how effective they are. This is another paper filling in more of the details, particularly relating to the Pfizer-BioNTech vaccine-BNT162b2. It is highly technical; but the good news is that it clearly shows good maturation of the immune response following vaccination, which is likely to provide both long term and broad immunity, which will remain effective against vaccine variants,” he clarified.

“Note that this paper only studies the Pfizer BioNTech vaccine. It does not compare this vaccine with other vaccines, so we do not know if other vaccines are as good, better, or not as good as BNT162b2 in these respects,” Dr English cautioned.

On 24 May 2021, Professor Ali H. Ellebody’s team from the Washington University at St Louis published a paper titled- SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans, in the journal Nature, conveying another piece of good news.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.