People with immunocompromising conditions have been shown to have a reduced response to COVID-19 vaccines and therefore are likely to be less well protected as borders open up over the next few months. An additional COVID-19 vaccine dose will offer better protection against severe disease in these groups. This ATAGI advice is timely as the risk of contracting a COVID-19 infection will increase as public health measures are relaxed and international travel resumes.

This is welcome news as evidence shows patients with significant immunosuppression mount a poorer response to vaccines and the response is of a shorter duration. Age and other factors also affect this. Many countries have adopted the third (booster) dose for immunosuppressed people and it is important and timely that Australia has done this also.

Currently we do not know the minimal antibody response required to produce effective protection against COVID-19 (correlate of protection) or how this response is affected with subsequent mutations to the virus.

ATAGI has decided against antibody testing at this time as the level of antibody response that correlates with protection is unknown.

Individuals who are significantly immunocompromised are very likely to have generated little or no antibody response following vaccination against COVID-19.

The measurement of antibody titres in this group would therefore still be of value to determine if any antibodies were produced and provide some indication if booster vaccination likely offer any additional protection.

The requirement of when and if booster vaccination might be of value does require the examination of neutralising antibody levels in vaccinated individuals.

This process allows the evaluation of the immune response to vaccination (i.e. did the individual respond to the vaccine and produce antibodies), how strong was the response (i.e. what concentration of antibody was produced) and how long is this response maintained.

It is also important to remember that vaccination does not equal immunisation and that antibody response generated to COVID-19 vaccination can be affected by several factors which include:

• Vaccine type (i.e. Pfizer, Modern, AstraZeneca)
• Time since last vaccination
• Prior COVID-19 infection
• Age (immune response decreases with age)
• Gender (females shown to have better responses than males)
• Medications used regularly (e.g. those that reduce immune response such as NSAIDs, steroids, chemotherapy and transplant drugs)
• Health status (i.e. autoimmune disorders, immunocompromised or history of poor response to vaccination)
• Lifestyle factors (e.g. smoking and chronic stress are immunosuppressive)

Antibody response following vaccination is of obvious interest to guiding government policy on booster vaccination but also has implications as to whether a significant percentage of the population responded appropriately to vaccination.

Individuals who are severely immunocompromised at the time of vaccination will be an obvious part of the population where significant levels of protective antibodies against COVID-19 were not achieved, hence the reason for booster vaccination.

The unknown in this approach is whether or not the original vaccination or subsequent booster will act to induce any antibody response.

If antibody levels are not examined in this group that the value of the suggested intervention remains unknown.

The data from overseas is accumulating and very clear that waning of immunity occurs by 5-6 months after the second dose, for both Pfizer and AstraZeneca. The waning is greater for older adults, and there is even waning of effectiveness against hospitalisation and death now. For immunosuppressed people, the response to 2 doses may be poor, and studies show good boosting with a third dose.

For long term control of COVID and a return to normal, all countries need to be able to pivot rapidly as the evidence changes, so it is very welcome news that ATAGI has made this recommendation.  We do need health worker boosters considered urgently, as most front line workers were vaccinated in February and March, and we have seen multiple infections in fully vaccinated health workers, including critical illness and at least one needing ventilation in ICU.  The re-opening of society will stress the health system, and we need health workers still standing – their safety is a priority.

A peak of vaccination occurred in the general community in August, so waning immunity will be noticeable by February 2022, and I hope that boosters for older adults are in place by then. Many older people got vaccinated early, especially those in residential aged care, so they may be at risk now. To avoid aged care outbreaks as we open up, we must address boosters for people in 1a and 1b, and then all older adults.

I will be one of the people potentially getting the booster shot! Very quickly…

This is very welcome news from ATAGI. There are a significant number of people in the community who are immunocompromised for a range of reasons, and the data is very clear about the beneficial effects of booster doses within this community.

In the context of primary immunodeficiencies, a group of >450 inherited immune disorders, studies have assessed immune responses following the 2nd doses of the RNA vaccines. In general, antibody responses are reduced in 50-80 per cent of these patients compared to the general population when measured 4-8 weeks after double vaccination.

These antibodies seemed to be less able to inhibit binding of the SARS-CoV-2 spike protein to the ACE2 receptor on human cells, suggesting they are potentially less effective at neutralising the coronavirus compared to similar antibodies detected in healthy vaccinated individuals. My expectation is that a lower antibody response in individuals with primary immunodeficiencies can continue to be increased by subsequent vaccination. A 3rd shot is a good idea for individuals with primary immunodeficiencies.

The recommendation by ATAGI of a third booster dose in immunocompromised individuals seems sensible as these individuals have a 1.5-2.0 times higher risk of death than the general population while having lower vaccine responses. Support for the third dose comes largely from evidence this dose increases antibody levels rather than direct evidence of improved clinical outcomes, but the data on clinical outcomes that is available is supportive of this strategy.  

There continue to be uncertainties regarding mix and match vaccine strategies, particularly for individuals primed with adenovirus vaccines and then boosted with mRNA or vice versa, but there is no reason to believe this might not be effective although safety and tolerability of different mix and match regimes still needs more study.

What is the need for booster shots for immune-compromised individuals?

"People who are moderately to severely immunocompromised make up about 3-5 per cent of the adult population and are especially vulnerable to COVID-19 because they are more at risk of serious, prolonged illness. Studies indicate some immunocompromised people don’t always build the same level of immunity after vaccination the way non-immunocompromised people do, and they may benefit from an additional dose to ensure adequate protection against COVID-19. There are studies in the US showing fully vaccinated immunocompromised people have accounted for a large proportion of hospitalized “breakthrough cases,” and that suggests immunocompromised people are more likely to transmit the virus to household contacts. It is vital that this group receive booster doses to break the transmission cycle."

How do vaccines generally work?

"The basic mechanism by which vaccines work is simple: Vaccines create immunity in an individual by introducing a weakened or killed form of the pathogen that make us ill - such as bacteria or viruses - or its toxins or one of its surface proteins. The vaccine induces acquired immunity so that when your body encounters the real disease-causing agent it is ready to mount a defence.

There is a collective social benefit in a high vaccination coverage. For most diseases, the greater the proportion of people who are immunized, the better protected is everyone in the population as the disease transmission can be reduced or stopped. Herd immunity is a community protection that is created when a high percentage of the population is vaccinated, such that it less likely that the infectious disease spreads. Herd immunity provides a protective barrier, especially also for those who cannot be vaccinated. These include vulnerable groups such as babies too young to be vaccinated or immune-compromised children who are the first potential victims of low vaccination rates. When a person is immune to a disease they can act as a barrier to slow down or prevent the transmission of disease to other people. When the number of people in a population that are immune against a disease is reached, such that a disease no longer persists in the population, this is called the herd immunity threshold (HIT)."

Vaccine immunity duration, waning of immunity

"The duration of immunity (protection against disease) varies with different diseases and different vaccines. Lifelong immunity is not always provided by either natural infection (getting the disease) or vaccination. The recommended timing of vaccine doses aims to achieve the best immune protection to cover the period in life when vulnerability to the disease is highest. Many vaccines used today are relatively new and data concerning the length of time that they give protection is continually being updated.

The immunity from vaccination wanes over time. Most of the time, the first shot of vaccination builds immunity against the disease, it primes our immune system to ‘learn’ about that particular pathogen (from which the vaccine is based). The subsequent booster shots are vital (in some cases more than 2) in improving the defence against that particular pathogen (antibody levels). It acts as a ‘reminder’ against the pathogen. The efficacy of a particular vaccine also depends on factors such as age, certain diseases which immunocompromises us including drugs and emergence of a mutated strain from the original strain the vaccine was based on."

What about COVID-19 vaccines?

"The COVID-19 vaccines currently in use protect against the virus in slightly different ways. Most target the coronavirus’s spike protein, which it uses to gain entry to our cells. But some deliver the instructions for making the protein in the form of messenger RNA (Pfizer, Moderna). Some deliver the spike protein itself (Novavax). Some use another harmless virus to ferry in the instructions for making it, like a Trojan horse (Johnson & Johnson, Oxford-AstraZeneca, Sputnik V). Some offer up whole inactivated virus (Sinopharm, Sinovac).

We are learning every day about our immune response against COVID-19 and the information we get from the vaccination is in real-time. From recent evidence, we know that two doses of vaccines are important to give the fullest protection and teach the body to make antibodies and T cells (an important component of our adaptive immunity) to block and kill the virus."

Do emerging new variants of concern and variants of interest change the vaccine protection equation?

"The COVID-19 vaccines that are currently in development or have been approved are expected to provide at least some protection against new virus variants because these vaccines elicit a broad immune response involving a range of antibodies and cells. Therefore, changes or mutations in the virus should not make vaccines completely ineffective. In the event that any of these vaccines prove to be less effective against one or more variants, it will be possible to change the composition of the vaccines to protect against these variants.

We do know that the current batch of vaccines trigger our immune systems to produce cells which protect against severe illness from COVID-19. These include “killer” T Cells, which recognise virus-infected cells and kill them, and so-called “B memory” cells that remember the virus and call the immune system into action should it attempt to infect a person after vaccination. The idea is that these B memory cells will stimulate an immune response that will neutralise the coronavirus before it is able to make you unwell, or at least severely unwell.

So far, research shows that the immune response from the existing COVID-19 vaccines remains strong for at least six to eight months. It is, of course, important to remember that COVID-19 vaccines only really got under way in December 2020, so data about their long-lasting effectiveness is still being gathered and it is likely that as time goes by, we will see that their effects last longer than this.'

Why is that?

"Stopping the spread at the source remains key. Current measures to reduce transmission, including frequent hand washing, wearing a mask, physical distancing, good ventilation and avoiding crowded places or closed settings, continue to work against new variants by reducing the amount of viral transmission and therefore also reducing opportunities for the virus to mutate. Scaling up vaccine manufacturing and rolling out vaccines as quickly and widely as possible will also be critical ways of protecting people before they are exposed to the virus and the risk of new variants. Priority should be given to vaccinating high-risk groups everywhere to maximize global protection against new variants and minimize the risk of transmission.

Moreover, ensuring equitable access to COVID-19 vaccines is more critical than ever to address the evolving pandemic. As more people get vaccinated, we expect virus circulation to decrease, which will then lead to fewer mutations. Vaccines are a critical tool in the battle against COVID-19, and there are clear public health and lifesaving benefits to using the tools we already have. We must not put off getting vaccinated because of our concerns about new variants, and we must proceed with vaccination even if the vaccines may be somewhat less effective against some of the COVID-19 virus variants. We need to use the tools we have in hand even while we continue to improve those tools. We are all safe only if everyone is safe."

Breakthrough infections:

We're all aware of the damage caused by the second/third wave of coronavirus. Now, amid fears of a possible third wave, experts believe following COVID-appropriate behaviour and getting oneself vaccinated should be prioritized at all costs.

But considering the fact that many fully vaccinated individuals are contracting the virus, people have started to doubt vaccine effectiveness and have become more hesitant. That said, researchers have been conducting studies to answer why such breakthrough cases are occurring on a regular basis. A breakthrough infection occurs when a person contracts a virus even after being fully vaccinated against it. He or she either remains asymptomatic or develops mild to moderate symptoms, while some even may succumb to the virus, but it is believed to be a rare occurrence.

Role of the immune system?

"When you get infected with the coronavirus infection, your body produces strong immune responses to fight the deadly pathogen. Even when you receive your COVID vaccine, it activates your immune system to produce virus-fighting antibodies. All these processes indicate that a person's immune system plays an important role in determining how well protected they are from infections. That said, people who have a compromised immunity may be more prone to SARS-CoV-2 infections, even when they're fully vaccinated. This has also opened up discussions around the need for vaccine boosters, also known as the third COVID vaccine dose. Given that fully vaccinated people are also getting infected with the virus, experts have signalled towards the possibility of waning immunity.

We must first understand, vaccination triggers our immunity at 2 different levels: an early B-cell mediated antibody response and a delayed T-cell mediated response. As explained before, the sustainability of vaccine-related immunity is dependent on how the individual responds to the vaccine, how efficient and effective the T cell response is going to be, whether the virus mutates over time to evade the kind of antibodies produced by the primary vaccination. Keeping all these factors into consideration, vaccination-induced immunity may wane in terms of antibody levels over time as what we are seeing in real world data from Israel where there is a surge infection although the majority of the people are vaccinated.

Vaccine boosters have gained a lot of momentum in recent times. Considering breakthrough infections have become prevalent and new variants continue to emerge every now and then, the demand for a booster dose is increasing. The administration of a booster shot is expected to re-expose a person's immune system to the immunizing antigen, the memory of which (following previous doses) could have been lost over a period of time. Most vaccines have a certain time period beyond which another shot is required in order to reactivate the immune system to produce antibodies, providing protection against a particular disease. All existing COVID-19 vaccines have been recently developed and each vaccine has been made distinctly. Depending on clinical trials and findings, vaccines that are producing antibodies for a duration of 8 months to a year may only require booster shots every few months to keep the immunity going.

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