COVID Vaccination After the Pandemic's Fourth Wave: The Debate Over 3rd and 4th Doses

COVID-19 vaccination was discussed by Hacettepe University Faculty of Medicine's Department of Microbiology and Infectious Diseases specialist Prof. Dr. Murat Akova in Infectious Diseases and Clinical Microbiology (IDCM), where he wrote a noteworthy editorial. We share a translation of that article below:

As of August 21, 2021, more than 32% of the world's population had received at least one COVID-19 vaccine dose, and nearly a quarter was fully vaccinated.

However, only 1.4% of the population in the developing world had received at least one dose. As the pandemic devastates unvaccinated communities, a new wave of disease is emerging in countries with high full-vaccination rates. At least three factors may be responsible for the latter situation:

1. New variants, such as delta, are emerging that are far more contagious than their predecessors and more resistant to antibodies generated by both natural infection and existing vaccines
2. Relaxation of preventive measures in the community, such as mask use and public gatherings, largely because of the initial confidence provided by vaccination
3. Immunity waning over time after the initial vaccination course

Although the term “pandemic of the unvaccinated” appropriately describes the current situation, as a substantial proportion of the most severe cases and deaths still occur in unvaccinated people, recent reports show that fully vaccinated people can also become infected with high viral loads. Different vaccines' ability to generate various types and strengths of immunity makes it more complicated to offer an evidence-based vaccination strategy.

In a letter published in this issue of the journal, Azap and colleagues reported that 39 of the 62 healthcare workers at their institution who contracted COVID-19 (63%) had been fully vaccinated with CoronaVac (China, Sinovac; an inactivated SARS-CoV-2 vaccine). All had mild disease, and no deaths were reported. SARS-CoV-2 variant information was unavailable, but the alpha variant was probably predominant in Turkey during the reporting period. The only placebo-controlled randomized trial of CoronaVac reported 83.5% overall efficacy and 100% protection against mortality (death) over a median follow-up of 43 days. Real-world data on CoronaVac from Chile showed vaccine effectiveness of 90% against intensive care unit admission, 86% against mortality and 66% against symptomatic disease.

Full immunization with CoronaVac was also highly effective in preventing severe disease and death when used during a local outbreak caused by the delta variant in China. Taken together, these data suggest that CoronaVac can provide strong protection against severe disease and death, at least in the short term. Unpublished observations in Turkey support these findings.

The delta variant has become predominant, and at least some vaccinated people are now more than eight months past their initial vaccination; the entire scenario is changing. Recent reports show that the delta variant can also infect fully vaccinated people, and that mRNA-based vaccines given as a full course are associated with viral loads similar to those in unvaccinated people. Several countries, including Israel, France and the United States, claiming that immunity wanes some time after vaccination, have launched third-dose campaigns, initially in immunocompromised populations and now across the whole community. The situation in Turkey is somewhat different. Turkey began vaccinating the population with CoronaVac in mid-January 2021, and the Pfizer-BioNTech vaccine became available in early April. Thus, more than six months have passed since those vaccinated early completed their vaccination schedules, and anecdotal reports indicate infections in this group that, although rare, can be severe or fatal. Turkey's Ministry of Health therefore recommended a third vaccine dose for all healthcare workers and people over 50 who initially received two CoronaVac doses. The third dose was provided as homologous vaccination (with CoronaVac) or heterologous vaccination (with Pfizer-BioN-Tech). People who contracted the disease more than three months ago (one month for the time being) are also eligible for a two-stage vaccination schedule with a vaccine of their choice.

Finally, a highly controversial recommendation, the first of its kind, arrived: a 4th vaccine dose!

From Turkey's Ministry of Health: a fourth vaccine dose is recommended for those who have received two CoronaVac doses and a third Pfizer-BioNTech dose. Although this proposal has no scientific basis, as acknowledged by the health minister himself, it is a prerequisite for people traveling to countries where CoronaVac is not an approved COVID-19 vaccine but is a two-stage vaccine. The Pfizer-BioNTech vaccine is considered eligible for full vaccination. There is no evidence on the safety of 4 vaccine doses; however, data are available on people who initially contracted the disease and subsequently received one or two Pfizer-BioNTech doses. Data from people who previously had COVID-19 showed that the first vaccine dose substantially increased neutralizing antibody levels, while the second dose did not increase them further. Therefore, if the first two CoronaVac doses are considered to mimic immune priming through natural infection, a four-dose schedule may be of no use, particularly when given at short intervals.

Because different vaccines have not yet been compared head to head, it is scientifically incorrect to compare the effectiveness of different COVID-19 vaccines. However, because the initial level of neutralizing antibody production with inactivated vaccines is far lower than with mRNA vaccines, the decline in neutralizing activity over time may be assumed to occur earlier with inactivated vaccines. Real-world observations of vaccine effectiveness may clarify this issue and provide evidence on the timing of booster dose(s). In this respect, Turkey has a unique opportunity to provide evidence on CoronaVac effectiveness and how it changes over time, as a large population was fully vaccinated with this vaccine more than six months ago. Detailed analysis of vaccine effectiveness and making the data publicly available would increase public confidence in the vaccination schedules offered and undoubtedly help reduce vaccine hesitancy in the community.

An Additional Scientific Development Outside the Article: Emerging Infectious Disease published a study in September 2021 that found that 36% of people in the United States who had contracted COVID-19 had no antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their blood. People who have had COVID-19 should therefore not feel reassured that they will not become infected again, and health policies should not be guided in that way. In conclusion, full vaccination and masks remain the best way to protect against COVID-19.

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RELATED TOPICS

• Covid-19: Current Statistics for the World and Turkey
• Latest News and Scientific Developments on Coronavirus

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