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Dear Editor The current epidemic of the novel Coronavirus disease 2019 (COVID-19) risen from Wuhan, China, turned to a worldwide concern because of its incubation period (2-14 days) and its high transmission rate. The first cases of the infection were reported in December 2019 in Wuhan with symptoms like pneumonia with an unknown reason. Very soon it was known as a novel kind of Coronavirus on 31 December 2019. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the main viral agent of this disease, is belonging to betacoronavirus genera, Coronaviridae family, an enveloped positive sense RNA virus. Like SARS-CoV, SARS-CoV-2 attacks the organism by binding to the angiotensin-converting enzyme 2 (ACE2). Recently, some reports of SARS-CoV-2 infection have been shown that the virus is found not only in the respiratory tract but also in the gastrointestinal tract. In recent year, SARS-CoV-2 is still infecting populations that lack immunity to the virus, causing significant disease and mortality (1, 2). Immunity to SARS-CoV-2, either through natural infection or through vaccination, to some extent protects and reduces the risk of significant clinical consequences. For example, it has been estimated that improved seropositive individuals can have up to 89% protection against re-infection (3) and that vaccine efficacy has been reported to be 50 to 95% (4). However, the duration of the created immunity period is not known and over time, this immunity weakens (5, 6), in addition, there is concern about the escape of new variants from the immune system (7). An important question here is to identify the immune link with protection against SARS-CoV-2 and thus predict how these changes will affect the clinical outcome of the disease. Neutralizing antibody titer is an important predictor of the effectiveness of vaccines in development. Studies show that the level of neutralizing antibodies decreases over time and a booster may be needed within a year. However, protection against the severe form of the disease may be significantly longer. It can be said that the development of a strong or weak humoral response depends on the interaction of the virus and the host and the inflammation that occurs. If the challenge is low, the antibody produced has poor performance, but if the challenge is high, the antibody produced is more functional and responds more aggressively to re-exposure to the pathogen. In addition, cellular immune responses can play a prominent role in this regard (8). Therefore, if existing vaccines, such as natural infections, are able to stimulate the cellular immune response in addition to producing neutralizing antibodies, the immunity persistence of the vaccine will also increase. Another question that arises is whether determining the antibody titer after a natural infection or vaccination can be a correct marker of the state of protection against infection? Antibodies act as markers of infection and, if persisted, can lead to long-term immunity. In most clinically approved vaccines we measure the binding antibody titer, while this is a neutralizing antibody titer that indicates how immunogenic is a vaccine. An antibody, in addition to binding to the desired antigen, must also be able to neutralize that antigen, either by blocking the infection by preventing the pathogen from binding to the receptor or by stimulate immune cells for clearance and disease control, which should also be considered in vaccine studies. In addition to antibody titer and function, knowing how antibody function is related to cellular immunity and the nature of T and B cell immunity is essential to realizing long-term protection against re-infection (9). It is not yet known how some people get re-infected despite having antibody titers. Can the presence of specific antibodies against other viral antigens compensate for the low titer of functional RBD specific antibodies? The answer is no. Experiments show that when the Ab-mediated complement deposition (ADCD) and Ab-dependent neutrophil phagocytosis (ADNP) tests were performed, virus neutralization was seen only in individuals with high IgG antibody titers against the RBD region. Therefore, it was concluded that only antibodies against RBD are neutralizing (10). However, it cannot be said that a high titer of anti-RBD antibody means high immunity because not all antibodies against RBD are neutralizing. Does it mean that there is no protection against re-infection if the antibodies lack good binding or function? We cannot say for sure because the role of the T cell, which acts as a strong immune responder to coronavirus disease 2019 (COVID-19), cannot be ignored. Suppose we measure the antibody titer in a number of volunteers at time T0 (test start time). Are only symptomatic people positive for neutralizing antibodies? According to an experiment conducted by YC Bartsch et al. (9) asymptomatic individuals also had specific antibodies against RBD with a specificity of over 99.5% by enzyme-linked immunosorbent assay (ELISA). This means that this antibody was present in both symptomatic and asymptomatic individuals, but its titer was higher in symptomatic individuals. After tracking subjects for antibody titers after a certain period of time, a small number of participants completely lost their antibody response, and in the remaining individuals, almost half of the subjects had decreased antibody titers and the other half had a dramatically increased antibody titers. This observation can be justified in two ways, first, that these people differed in the length of time they spent with the infection, and second, that people with elevated antibody titers may be re-exposed to the infection. Knowing this, it can be concluded that measuring the antibody titer after infection or vaccination will not give us accurate information about the level of protection against SARS-CoV-2 infection. Routine clinical laboratory methods such as ELISA will never be able to make sure that the antibodies produced in your body are neutralizing or not, because this requires specialized neutralizing tests. In addition, knowing the initial antibody titer, it is not easy to estimate that the rate of antibody reduction will be faster or slower. Therefore, models that predict immune responses to infection need to determine the link between the protection provided by expanding vaccines. Because in different studies, a single method has not been used to measure the neutralizing antibody titer, there is a need for data normalization methods to better compare the results. In addition, we suggest that in addition to measuring the neutralizing antibody titer, the responses of memory T and B cells, which are associated with high protection against SARS-CoV-2, be measured so that we can have a better prognosis for neutralization.