Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and its disease (Covid-19) has afflicted millions of people in a worldwide pandemic and on its path changed the lives of billions of people. Vaccines that are safe and effective for Covid-19 are needed urgently as part of a plan to solve the pandemic. An array of modalities including novel techniques are being utilized as vaccine platforms such as mRNA (manufactured by Moderna and BioNTech/Pfizer), inactivated virus (Sinovac, Sinopharm), viral vector (Oxford/AstraZeneca, Gamaleya, Janssen/ Johnson&Johnson, CanSino), and protein subunit (Novavax) with each reporting a 63-95% protection against Covid-19 after a two-dose regimen in persons 16 years of age or older [1-3]. Health care workers (HCW) were the first group to be vaccinated as HCW was considered a high-risk group. By March 2021, 1.436.994 Indonesian healthcare workers, or 97,84 % of the workforce, have received their second dose of the vaccine [1,4]. Our hospital was a tertiary referral and teaching hospital also complied to our national regulation by vaccinating our staff. Studies identified that Covid-19 vaccines generally prevented hospitalization and death, but its ability to prevent transmission is less reported [1-3]. We aim to report two clusters of COVID-19 among HCW post-vaccination.

Method

The study was a retrospective case series of two consecutive clusters in a government-owned tertiary referral and teaching hospital in Indonesia from March 15th to May 31st, 2021. Institutional ethical clearance and patient publication consent were obtained number LB.02.01/X.6.5/189.A/2021, and data was gathered from the hospital staff Covid-19 tracing database. The database included all HCW such as consultants, residents, nurses and non-HCW such as administration staff and security staff. No intervention was done on the subjects, and observation was done after the hospital has conducted its mandatory COVID-19 vaccination program in January 2021.

Results

The hospital had 5115 HCW consisting of 3688 hospital staff and 1427 students such as residents, sub-specialistic trainees and medical students. The vaccination program started on January 20th, 2021. The first cluster started when two anesthesia residents complained of fever and cough at the end of March 2021. They were put on mandatory self-isolation, and Polymerase Chain Reaction (PCR) testing concluded that both doctors were positive for SARS-CoV-2 (Figure 1). The first doctor, a male (P1), had received his second Covid-19 vaccination on February 15th, 2021. However, the second doctor, a female (P2), was a volunteer on the Covid-19 double-blinded vaccination trial in our local affiliated University in December 2020 and, after confirmation, had received a placebo. Contact tracing revealed that P1’s wife (P3) was also symptomatic and tested positive for SARS-CoV-2 later that week. The wife was a doctor who also had received two doses of the Covid-19 vaccine on February 10th, 2021. The Covid-19 vaccine they received was Corona-vac ( Sinovac Ltd, China). These patients represented the first cluster of HCW with Covid-19 infection after two doses of vaccination in our hospital.

All three patients had an antibody test carried out, and only P1 had a positive IgG for SARS-CoV-2 with a titter of 16.730 AU/ml. P1 and P3 were hospitalized in a district hospital because they were unable to self-isolate in their homes. During hospitalization, they received remdesivir for five days, although their symptoms were relatively mild. P1 tested negative after eleven days, P3 tested negative after eleven days, and P2 tested negative after 29 days, in which all staff was able to return to work afterward. The second cluster consisted of five anesthesia residents who complained of fever with upper respiratory tract symptoms on the third week of May 2021. (Figure 2) Four subjects in the second cluster were vaccinated, and one subject (S4) was not vaccinated because S4 had uncontrolled hypertension. The vaccine they received was Corona-vac (Sinovac Ltd, China). All vaccinated subjects in the second cluster showed mild symptoms that did not require any hospitalization, but S4’s symptoms progressed, and he was admitted to critical care on the 5th day of his symptom. During his stay, S4 received high flow oxygenation and plasma convalescence therapy. The first subject (S1) was previously infected with SARS-CoV-2 in November 2020 and was vaccinated in March 2021. Until early June 2021, all members of the second cluster remained positive with SARS-CoV-2 and could not provide medical service.

We also presented data gathered from the general picture of active infection in our city, vaccination status, and positive HCW in our hospital as a tool for further analysis. (Figure 3) Between January to April 2021, there was a sharp increase of active cases in our city, and while the vaccination process is being carried out, an 60% second dose rate coverage of our HCW was achieved at the end of February 2021 by means that a 14-28 days to positive protective antibody would have been detected by the second week of March. Our data suggest a trend of decreasing infection rates among HCW after vaccination.

Discussion

Several studies have identified viruses from aerosols and surfaces after inoculation during the early times of the pandemic. However, real-world studies have shown that the environmental SARS-CoV-2 virus is deficient, and few have isolated viable viruses; thus, infection from this source is unlikely. Reports of clusters, which are very commonly present in Covid-19, such as our case, indicated that respiratory transmission is dominant, with proximity and ventilation being critical determinants of transmission risk [5]. Our cluster members’ proximity is frequently close since they all worked together in anesthesia. Anesthesiologists are a high-risk HCW group since they routinely perform aerosol-generating procedures that potentially transmit SARS-CoV-2. The clusters also shared many personal activities such as eating, scrubbing up, sharing locker time or sharing sleeping quarters during night shifts. The Centre for Disease Control (CDC) has issued a statement that fully vaccinated people can gather on indoor conditions without masks, but our reports suggest that liberal practice may not be viable enough [6]. We also need to consider that the CDC statement was clarified to only three mRNA vaccines (Pfizer, Johnson & Johnson and Modena). Further studies regarding the effectiveness of Corona-vac in preventing infection are needed.

P1 in the first cluster had an active antibody during testing, providing partial protection from the virus and a shorter period of positive antigen test. Although HCW was asymptomatic, persistent positive results caused long sick leaves among HCW, as in our hospital [7,8]. Interestingly, P3 was vaccinated but had a negative antibody test and a shorter positive antigen test than P2, who received a placebo. Possibly, a slight titter of antibody undetected on a rapid antibody test still has a protective effect. Note that for S4, both previous infection and vaccination did not protect from a second infection. Some studies show a general concern about the possibility that a previous infection does not provide immunity, and vaccines will only reduce symptoms during a second infection rather than prevent that infection altogether. This phenomenon could effectively turn vaccinated people into asymptomatic carriers and putting vulnerable populations at risk [5-9].

Further studies must understand how the immune system responds to natural infection and vaccination. Local community infection was high from March to April 2021, translating to a higher HCW infection probability. Interestingly, our HCW infection rate was low compared to January to February 2021. Consistent with our findings, a study in California at the end of March 2021 reported that from 28.184 HCW who received the second dose of the Covid-19 vaccine, 37 HCW tested positive, with only 7 of them tested positive 15 days or more from the second vaccination [9,10].

Another vital variable to discuss is the spread of the delta variant in Indonesia. The B.1.617.2(delta) variant of the SARS-CoV-2, first detected in India. By May 19th, 2021, this variant was detected in 43 countries and caused an unprecedented peak in infection rates in speed, number and severity [11]. Laboratory data indicated that the delta variant was characterized by the spike in protein mutations Δ157-158, L452R, T478K, D614G, P681R, and D950N.1 Several of these mutations may affect immune responses directed toward the key antigenic regions of the receptor-binding protein (452 and 478) and deletion of part of the N-terminal domain.23 P681R is at the S1–S2 cleavage site, and it appears that strains with mutations at that site may have increased replication, which leads to higher viral loads and increased transmission [12]. Delta variant was resistant to neutralization by some drugs, including bamlanivimab, which impaired the drugs ability to bind to the viruses mutated spike. Sera from convalescent patients collected up to 12 months post symptoms were fourfold less potent against variant Delta than variant Alpha (B.1.1.7). Sera from individuals having received one dose of Pfizer or AstraZeneca vaccines barely inhibited variant Delta. Administration of two doses generated a neutralizing response in 95% of individuals, with titers 3 to 5 fold lower against Delta than Alpha. Thus, variant Delta spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes. These findings are concerning since natural infection and vaccination may not protect against the delta variant [12-13].

However, “real world” findings in countries with increasing delta variant cases, such as the United Kingdom and the United States, shows promising results where a high positive case is not accompanied by the increase in mortality which suggests a potential success of their vaccination programs with at least 50% of the population being vaccinated once. This report suggests that mRNA vaccines used in the UK and US, mainly Pfizer and Moderna, effectively reduce mortality due to the delta variant, and a close study should be done on the Sinovac/Sinopharm/Coronavac vaccines, which relies on the weakened live virus [14].

The cluster of cases in our hospital must be approached carefully, and vaccination must not be considered a failure yet. Our report only shows a small group of patients, and a more extensive observational study is needed to conclude. It is imperative to understand that the vaccines against SARS-CoV-2 might act against infection, disease, or transmission of the virus, and a vaccine capable of any of these elements could contribute to disease control. Studies have also shown that the time and concentration of antibody is not equal in some patients. A booster may be needed to amplify immunity in several cases; thus, evaluating blood immunity levels may be needed to understand the vaccine’s effectiveness [1,8-10]. Although the most critical end-point clinically is not to stop infection but to protect a person against severe disease and death caused by SARS-CoV-2, sick leaves burden the health system for the health care workers. Studies have shown that many Covid-19 patients may still test positive for up to 90 days after the first test. However, the World Health Organization (WHO) and CDC recommended that HCW go back to work after 14 days of isolation and symptoms free, but our hospital still required a negative PCR test result. Sick leaves add a burden to the remaining staff and reduce hospital effectiveness in giving health services, especially in higher infection times when all workforce is needed. Maintenance of basic health protocols such as masks, handwashing, and social distancing is still essential since a sick HCW, although not severe, still needs sick leaves. It will be interesting to observe how the Indonesian government plans to give their HCW with the third booster of m-RNA vaccine will provide a better outcome . Thus, basic health protocol is essential for the time being, vaccinated or not.

References

1. Ophinni Y, Hasibuan AS, Widhani A, Maria S, Koesnoe S, et al. (2020) COVID-19 Vaccines: Current Status and Implication for Use in Indonesia. Acta Med Indones 52: 388-412.
2. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, et al. (2020) C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383: 2603-2615.
3. Zhang Y, Zeng G, Pan H, Li C, Hu Y, et al. (2021) Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 21: 181-92.
4. Peta Sebaran Covid-19 Indonesia. Indonesia Covid-19 task force 2021.
5. Meyerowitz EA, Richterman A, Gandhi RT, Sax PE (2021) Transmission of SARS-CoV-2: A Review of Viral, Host, and Environmental Factors. Ann Intern Med 174: 69-79.
6. When You’ve Been Fully Vaccinated. Centre for Disease Control United States 2021.
7. Gousseff M, Penot P, Gallay L, Batisse D, Benech N, et al. (2020) “Clinical recurrences of COVID-19 symptoms after recovery: viral relapse, reinfection or inflammatory rebound?.” Journal of Infection 5: 816-846.
8. Ledford Heidi (2020) “COVID-19 reinfection: three questions scientists are asking.” Nature 7824: 168-169.
9. Keehner J, Horton LE, Pfeffer MA, Longhurst CA, Schooley RT, et al. (2021) SARS-CoV-2 Infection after Vaccination in Health Care Workers in California. N Engl J Med 2021.
10. Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KRW, et al. (2021) What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis 21: e26-e35.
11. Dyer O (2021) Covid-19: Indonesia becomes Asia’s new pandemic epicentre as delta variant spreads BMJ 2021.
12. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, et al. (2021) Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021.
13. Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel-Benhassine F, et al. (2021) Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 2021.
14. WHO Coronavirus (Covid-19) dashboard. World Health Organization (WHO) 2021.