The complete effectiveness of COVID-19 vaccines has been questioned for some time now. This article presents a UK study highlighting COVID-19 breakthrough infections and the risk factors post-vaccination.

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The study

A large-scale UK study investigating COVID-19 breakthrough infections published online on September 1, 2021, in The Lancet Infectious Diseases journal showed that people who tested positive for SARS-CoV-2 after one or two vaccine doses had significantly lower odds of severe disease or hospitalisation than unvaccinated people did.

Researchers developed several effective vaccines against the SARS-CoV-2 virus. These vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, however, some people still become infected with SARS-CoV-2 after vaccination. This breakthrough infection is a very important area of study.

In the present study, the researchers aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of the post-vaccination illness. Vaccination against SARS-CoV-2 is a leading strategy to change the course of the pandemic worldwide.

The UK, the first country to authorise a vaccine against the virus and to license three vaccines as of July 2021: (Pfizer–BioNTech, Moderna, and Oxford–AstraZeneca), with good efficacy in phase 3 clinical trials were eminently placed to carry out this robust study.

Of the 67·1 million adults in the UK, by July 4, 2021, around 45·4 million people had received one vaccine dose and around 33·7 million people had received two doses. The UK data present an early insight into the real-world effectiveness of COVID-19 vaccines and the remaining challenges post-vaccination.

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Findings from the study (verbatim)

1. After two vaccines doses, the odds of hospitalisation were reduced by more than two-thirds and breakthrough infections were almost two times more likely to be completely asymptomatic.
2. The odds of long COVID-19 (symptoms continuing for 28 days or more after testing positive) were also reduced by more than half for people who received two vaccine doses.
3. People over the age of 60 who were frail or had underlying conditions had higher odds of a breakthrough infection, especially after only one dose.
4. The findings could have implications for health policies around timing between vaccine doses, potential COVID-19 vaccine booster shots, and for continuing personal protective measures, including mask-wearing and social distancing.
5. Using self-reported data from the UK COVID Symptom Study through the ZOE app from 8 December 2020 through 4 July 2021, researchers found that of more than 1.2 million adults who received at least one dose of either the BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCoV-19 (Oxford-AstraZeneca), or mRNA-1273 (Moderna) vaccine, fewer than 0.5% reported a breakthrough infection (6,030 positive cases after 1,240,009 first vaccine doses) more than 14 days after their first dose.
6. Among adults who received two vaccine doses, fewer than 0.2% experienced a breakthrough infection (2,370 positive cases after 971,504 second vaccine doses) more than seven days after their second dose.

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The UK COVID symptom study

The original data for the study emerged from The UK COVID symptom study. The health science company ZOE launched at the end of March 2020, the ZOE COVID Symptom Study app that is a not-for-profit initiative app with the scientific analysis provided by King’s College.

With over 4 million voluntary contributors globally, the Study is the world’s largest ongoing study of COVID-19 and is led by ZOE Co-Founder, Professor Tim Spector. The National Health Service (NHS) Wales, Welsh Government, the Scottish Government & NHS Scotland endorsed the study.

The ZOE symptom study group shared the data collected with and analysed by King's College London & ZOE research teams. The number of contributors to the UK COVID Symptom Study is increasing daily.

The team revealed while seeking cooperation from the contributors:

"By using this app you're helping and contributing to advance vital research on COVID-19. By combining your reports with software algorithms, we are able to predict who has the virus and so track COVID infections across the UK and now other countries. Your daily reporting is also being used to generate new scientific understanding of the very different symptoms the virus causes in different people. We are also studying the way that risks vary between individuals because of their own personal characteristics."

Professor Tim Spector, a professor of genetic epidemiology at King's College London is no stranger to such projects. For three decades, he has been leading a scientific study of 15,000 identical and non-identical twins as its director.

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The importance of the present Lancet study

The study's co-lead author Dr Claire Steves of King’s College London, UK, in a press release from the journal:

“We are at a critical point in the pandemic as we see cases rising worldwide due to the delta variant. Breakthrough infections are expected and do not diminish the fact that these vaccines are doing exactly what they were designed to do—save lives and prevent serious illness. Other research has shown a mortality rate as high as 27% for hospitalised COVID-19 patients. We can greatly reduce that number by keeping people out of the hospital in the first place through vaccination. Our findings highlight the crucial role vaccines play in larger efforts to prevent COVID-19 infections, which should still include other personal protective measures such as mask-wearing, frequent testing, and social distancing."

The researchers revealed that among those who did experience a breakthrough infection, the odds of that infection being asymptomatic increased by 63% after one vaccine dose and by 94% after the second dose. Researchers also found that the odds of hospitalisation were reduced by approximately 70% after one or two doses and that the odds of experiencing severe disease defined as having five or more symptoms in the first week of illness were lessened by approximately one-third. In addition, the odds of long COVID (having symptoms for 28 days or more after infection) were reduced by 50% after two doses.

Another notable fact is that for those who did experiences such as fatigue, cough, fever, and loss of taste and smell, symptoms after either one or two vaccine doses, almost all symptoms were reported less frequently than in unvaccinated people.

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Frail adults

1. In frail adults over the age of 60 years, the odds of a breakthrough infection after one vaccine dose were almost doubled, compared to healthy older adults.
2. Additionally, in older adults who had received their first vaccine dose but not their second, kidney disease, heart disease, and lung disease were the underlying conditions associated with a breakthrough infection.
3. The researchers also found that the risk of a breakthrough infection was related to the place a person lived, with people living in areas with the highest deprivation having the highest odds of a breakthrough infection following their first vaccine dose. The authors feel that this could be due to many underlying causes including closer living quarters and lower overall vaccination rates in those communities, making the virus more likely to be spread.

“The increased risks of breakthrough infections for frail, older adults especially those living in care homes or who require frequent visits to healthcare facilities and for other people living in deprived conditions reflect what we’ve seen throughout the pandemic. These groups are at a greater risk of exposure and are therefore more vulnerable to infection. Health policies designed to prevent infections, including policies around timing between the first and second dose and potential booster shots, should prioritise these groups,” co-author Dr Rose Penfold of King’s College, London cautioned.

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Limitations

The authors conceded that the study has some limitations:

1. The research uses self-reported data and therefore the reported co-morbidities, test results, and vaccination status could be inaccurate or incomplete, and individuals living in more deprived areas could be underrepresented.
2. These findings might not apply to all time-points post-vaccination, to settings with different proportions of SARS-CoV-2 variants, or to countries with different vaccination schedules.

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Expert comments

In a press release from Science Media Centre, London, Prof Penny Ward, Independent Pharmaceutical Physician, Visiting Professor in Pharmaceutical Medicine at King’s College London noted that this report is one of the first to provide information on breakthrough cases of COVID detected post-vaccination drawn from the 4.5million respondents that provide daily data using the ZOE app.

"This app is a self-reporting tool, and as shown in the data provided not all participants report daily and there is a relative excess of female participants, so it is not as completely representative of the UK population as a purist may like," Professor Ward cautioned.

"However this does not detract from the usefulness of the information provided, and we know from past experience that information provided by this group (for example the linkage between anosmia/dysgeusia and later testing positive for SARs CoV2) can be very helpful in providing early insight into public health policies. In this case, the information provided is helpful in understanding the potential need for booster vaccinations in a proportion of the frail elderly as we approach winter," she clarified.

“The data are broadly reassuring in confirming that illness associated with breakthrough infection tends to be less severe than illness occurring in unvaccinated people, and in particular that the risk of needing to be hospitalised following breakthrough infection is reduced overall by ~two thirds (from 10-9 to 3.6% after the first dose and from 7.4 to 2.2% after two jabs) compared to age and risk matched unvaccinated controls, with the greatest benefit among older people (>60) in whom double vaccination is ~80% effective in protecting against the need to be hospitalised," she reported.

"In addition, the proportion without symptoms ranged from ~1:4 to 1:8 (with more asymptomatic cases among older people) among the vaccinated compared to ~1:10 among the unvaccinated cases. Persistent symptoms lasting >28 days were not much affected in cases occurring after a single dose of vaccine, but the incidence was halved (from 11.4 to 5.2%) among the double vaccinated, suggesting for the first time that vaccination can protect against Long COVID both by preventing infection and then ameliorating illness experienced following breakthrough infection," she added.

"Regrettably the study did not contain information on illness associated with different variants, and the duration of the study (Dec 2020 to early July 2021) covered the alpha and early delta variant waves in the UK." She highlighted an important deficiency.

Question 1: Is the data on long-COVID robust? Is it just because vaccines reduce the risk of getting COVID in the first place or is there evidence here that there is more protection against long COVID than just that? 

She answered:

“Long COVID is explored in this study by assessing the proportion of cases with symptoms persisting for more than 28 days. However long COVID is still poorly understood and the persistence of symptoms post-infection, and their severity remains to be explored. It is however encouraging that the overall proportion of cases with persistent symptoms is reduced in patients that were previously fully vaccinated, which taken together with the milder overall illness and reduction in the need for hospital care demonstrates the additional worth of vaccination in reducing the severity of illness for individuals and reducing the burden on the NHS by lowering the number of people needing hospital care."

Question 2: Can the study methods allow robust conclusions to be drawn like “fully vaccinated people are almost twice as likely to have no symptoms than unvaccinated if they catch COVID-19”?

"While agreeing that that is what the data suggest she clarified that the population using the app is not entirely representative of the whole population, so the information might merit some detail." She qualified the statement- "About 1:5 people catching COVID after vaccination reported that they had no symptoms while only 1:10 people who had not been vaccinated reported having no symptoms.”

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.